Pharmacologically active thiourea and urea compounds

ABSTRACT

The compounds are substituted thioalkyl-, aminoalkyl- and oxyalkyl-thioureas and ureas which are inhibitors of histamine activity.

This is a division of application Ser. No. 451,333 filed Mar. 14, 1974,now U.S. Pat. No. 3,950,353, which is a continuation-in-part of Ser. No.290,584 filed Sept. 20, 1972, now abandoned, which is acontinuation-in-part of Ser. No. 230,451, filed Feb. 29, 1972, nowabandoned.

This invention relates to pharmacologically active compounds, topharmaceutical compositions these compounds and to processes for theirpreparation. The compounds of the invention can exist as the additionsalts but, for convenience, reference will be made throughout thisspecification to the parent compounds.

It has for long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyramine is a typical example) is believed to involve a receptorwhich has been designated by Ash and Schild (Brit. J. Pharmac. 1966, 27,427) as H-1. The substances of the present invention are distinguishedby the fact that they act at histamine H-2 receptors which, as describedby Black et al. (Nature, 1972, 236, 385), are histamine receptors otherthan the H-1 receptor. Thus they are of utility in inhibiting certainactions of histamine which are not inhibited by the above-mentioned"antihistamines". The substances of this invention may also be ofutility as inhibitors of certain actions of gastrin.

The compounds with which the present invention is concerned may berepresented by the following general formula; insofar as tautomerismaffects the compounds mentioned in this specification, the numbering ofthe nucleus has been modified accordingly; ##STR1## wherein A is suchthat there is formed together with the carbon atom shown an unsaturatedheterocyclic nucleus, which comprises at least one nitrogen and maycomprise a further hetero atom such as sulphur and oxygen, saidunstaturated heterocyclic nucleus being an imidazole, pyrazole,pyrimidine, prazine, pyridazine, thiazole, isothiazole, oxazole,isoxazole, triazole, triadiazole, benzimidazole or5,6,7,8-tetrahydroimidazo[1,5-a]pyridine ring; X₁ is hydrogen, loweralkyl, hydroxyl, triflouromethyl, benzyl, halogen, amino or ##STR2## X₂is hydrogen or when X₁ is lower alkyl, lower alkyl or halogen; k is 0 to2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; Y isoxygen, sulphur or NH; E is oxygen or sulphur; and R₁ is hydrogen, loweralkyl, benzoyl or di-lower alkylamino-lower alkyl or a pharmaceuticallyacceptable addition salt thereof. Y is preferably oxygen or sulphur,most advantageously sulphur. Preferably A is such that the nitrogen atomis adjacent to the carbon atom shown and, more preferably, such that itforms with the said carbon atom an imidazole, thiazole or isothiazolering. Preferably, X₁ is hydrogen, methyl, bromo, amino or hydroxyl andX₂ is hydrogen. One group of preferred compounds within the presentinvention is that wherein Y and E are sulphur, k is 1, m is 2 and R₁ ismethyl. Specific compounds which are found to be particularly useful areN-methyl-N'-[ 2-(4-imidazolymethylthio)ethyl]thiourea,N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl] thiourea,N-methyl-N'-[2-((5-bromo-4-imidazolyl)methylthio)ethyl]thiourea,N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea,N-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]-thiourea,N-methyl-N'-[2-((1-methyl-2-imidazolyl)methylthio)-ethyl]thiourea,N-methyl-N'-[2-(2-imidazolylmethylthio)-ethyl]thiourea,N-methyl-N'-[2-(2-thiazolymethylthio)ethyl]-thiourea,N-methyl-N'-[2-(5-amino-2-(1,3,4-thiadiazolyl)-methylthio)ethyl]thiourea,N-methyl-N'-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]thiourea andN-methyl-N'-[3-(2-thiazolylthio)propyl]thiourea.

The compounds with which the present invention is concerned wherein Y issulphur and k is 1 or 2 may be produced by processes which commence witha substance of the following general formula: ##STR3## wherein A, X₁ andX₂ have the same significance as in formula I except that X₁ may not be##STR4## but may additionally be (CH₂)_(k) _('Q;) k' is 1 or 2 and Q ishydroxyl, halogen or methoxy. In the first stage of these processes, thecompound of formula II is reacted with an amino-mercaptan of thefollowing FORMULA III:

    hs--(ch.sub.2).sub.m --NH.sub.2

wherein m has the same significance as in formula I.

When Q is halogen, this reaction may be carried out under strongly basicconditions, for example in the presence of sodium ethoxide or sodiumhydroxide. Since the substance of formula III is a primary amine it maybe necessary to protect the amino group, for example by a phthalimidogroup which may subsequently be removed by acid hydrolysis or byhydrazinolysis. When Q is hydroxyl or halogen it is found that thereaction will take place under acidic conditions e.g. in the presence ofa halogen acid such as 48% aqueous hydrogen bromide, or a halogen acidin the presence of glacial acetic acid. When Q is methoxy, the reactionwill also take place in the presence of 48% hydrogen bromide.

When k is zero, the corresponding first stage of the reaction is betweena nucleus directly substituted with a thiol or a thione and, underacidic conditions, 3-aminopropanol or, under alkaline conditions, a3-halopropylamine, the amino group being protected if required in thelatter case, e.g. by a phthalimido group which may be subsequentlyremoved by acid hydrolysis or by treatment with hydrazine.

The product produced by these processes is of the following formula IV,and may, of course, be in the form of the acid addition salt: ##STR5##wherein X₁ has the same significance as in formula II and A, X₂, k and mhave the same significance as in formula I. The free base of formula IVmay be obtained from the acid addition salt by treatment with anappropriate base e.g. an alkali metal alkoxide such as sodium ethoxideor an inorganic base such as potassium carbonate.

The compounds of formula I, where R₁ is hydrogen, Y is sulphur and E issulphur may be prepared from an amine of formula IV by reaction with anacyl isothiocyanate such as benzoyl isothiocyanate in an appropriatesolvent such as chloroform. Alkaline hydrolysis of these compounds, e.g.the benzoyl derivatives where R₁ is C₆ H₅ CO, with a reagent such asaqueous potassium hydroxide or aqueous potassium carbonate yields thecompounds of formula I wherein R₁ is hydrogen and Y and E are sulphur.

Compounds of formula I wherein R₁ is hydrogen, Y is sulphur and E issulphur may alternatively be prepared directly from the amine of formulaIV by reaction at elevated temperature with the thiocyanate of ammoniumor of a metal such as sodium or potassium.

The compounds of formula I where R₁ is lower alkyl or dialkylaminoalkyl,Y is sulphur and E is sulphur may be prepared from the amine of formulaIV by reaction with an isothiocyanic ester of formula R₁ -N=C=S in anappropriate solvent such as chloroform, ethanol, isopropanol,acetonitrile or water.

Alternatively the amine of formula IV may be converted by reaction withcarbon disulphide to the dithiocarbamic acid of the formula: ##STR6##wherein A, X₁, X₂, k and m have the same significance as in formula IVand R₃ is hydrogen, and then methylated to yield the compound of formulaV wherein R₃ is methyl. Finally, reaction of this methyl ester with anamine of formula R₁ NH₂, wherein R₁ is lower alkyl, yields the requiredcompound.

In the case of compounds of formula I wherein Y is oxygen, the processfor their production commences with a compound of formual VI (which mayitself be formed by treatment with thionyl halide of the correspondingalcohol resulting from the reaction of a haloakyl heterocyclic compoundwith the sodium salt of a diol) ##STR7## wherein A,X₁, X₂ and m have thesame significance as in formula I, k'is 1 or 2,k' + m is 3 or 4 and B ishalogen. This compound may be reacted with an alkali metal azide and theresulting product reduced, e.g. by hydrogenation over a platinum dioxidecatalyst, to yield an amine of formula VII in which k is 1 or 2 andwherein A, X₁,X₂ and m have the same significance as in formula I.##STR8##

The amines of formula VII in which k is zero are prepared by reacting ahalo-heterocycle under strongly basic conditions with1,3-dihydroxypropane, converting the resultant 3-hydroxypropoxy compoundwith thionyl chloride to the 3-chloropropoxy compound which on reactionwith sodium azide and reduction of the product yields the requiredamine.

The compounds of formula VII may be converted to the compounds offormula I wherein Y is oxygen and E is sulphur by methods analogous tothose described hereinabove for the conversion of the compounds offormula IV to those of formula I wherein both Y and E are sulphur.

The compounds of formula I wherein Y is NH and E is sulphur aresimilarly formed from a compound of formula VIII ##STR9## wherein theamino group in the alkylene chain may be protected when k is 1 or 2 andoptionally the terminal amino group may also be protected and A, X₁, X₂,k and m have the same significance as in formula I, except that X₁ maynot be ##STR10## but may additionally be (CH₂)_(k) Y(CH₂)_(m) NH₂.

The intermediates of formula VIII are prepared by a process whichcommences with a substance of the following general formula: ##STR11##wherein A, X₁, X₂ and k have the same significance as in formual I,except that X₁ may not be ##STR12## but may additionally be (CH₂)_(k)--halo. In this process, a compound of formula IX is reacted with adiamine of the following FORMULA X:

    h.sub.2 n--(ch.sub.2).sub.m --NH.sub.2

wherein m has the same significance as in formula I. This reaction maybe carried out under strongly basic conditions, for example in thepresence of sodium ethoxide or sodium hydroxide or in an anhydroussolvent such as dimethylformamide in the presence of sodium hydride.When k is 1 or 2 in formual IX, one of the amino groups of the diamineof formula X may be protected by a group which will be stable under theconditions of the reaction, for example a trifluoroacetyl or a formylprotecting group may be used when the reaction is carried out underanhydrous conditions. When the amino group in the alkylene chain in theresultant intermediate is protected for the process to prepare compoundsof this invention, which should then also be carried out under anhydrousconditions, the N-protecting group is finally removed e.g. by treatmentwith dilute hydrochloric acid.

Alternatively, when k is 0 the appropriate amino heterocyclic compoundmay be used as the starting material and reacted with a halophthalimidocompound of the following FORMULA XI: ##STR13## Hydrolysis orhydrazinolysis of the product of this reaction yields the compound offormula VIII wherein k is 0 and m is 3.

Compounds of formula I wherein E is oxygen may be formed from the aminesof formula IV, formula VII or formula VIII by treatment thereof with anisocyanate of formula R₁ NCO wherein R₁ is lower alkyl, benzoyl ordialkylaminoalkyl. The compounds of formula I wherein E is oxygen and R₁is hydrogen may be obtained by reaction of the said amines with sodiumor potassium cyanate.

As stated above, when Y is NH any N-protecting group on the NH may beremoved, e.g. in the case of N-formyl or N-trifluoroacetyl groups bydilute acid treatment. If no N-protecting groups have been used, amixture of the desired product of formula I and the correspondingbis-thiourea or bis-urea may be formed from which the former can beseparated e.g. by chromatography.

As stated above, the compounds represented by formula I have been foundto have pharmacological activity in the animal body as antagonists tocertain actions of histamine which are not blocked by "antihistamines"such as mepyramine. For example, they have been found to inhibitselectively the histamine-stimulated secretion of gastric acid from theperfused stomachs of rats anaesthetised with urethane, at doses of from0.5 to 256 micromoles per kilogram intravenously. Similarly, the actionof these compounds is demonstrated by their antagonism to the effects ofhistamine on other tissues which, according to the above-mentioned paperof Ash & Schild, are not H-1 receptors. Examples of such tissues areperfused isolated guinea-pig heart, isolated guinea-pig right artium andisolated rat uterus. The compounds of the invention have also been foundto inhibit the secretion of gastric acid stimulated by pentagastrin orby food. In addition to the above the compounds of the invention alsoshow anti-inflammatory activity in conventional tests such as the ratpaw oedema test at doses of about 500 micromoles/kg. subcutaneously.

The level of activity found for the compositions comprising thecompounds of the present invention is illustrated by the effective doserange in the anaesthetised rat, as mentioned above of from 0.5 to 256micromoles per kilogram, given intravenously.

Dose determination studies have been carried out in patients with pepticulceration who have been shown to have high basal gastric acidsecretion. Forty patients have been studied and the results indicatethat an oral dose of 200 mg. of metiamide, that isN-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea, givesrise in general to plasma levels which are associated with inhibition ofgastric acid and pepsin secretion. Twenty-two patients with pepticulcers who have high levels of basal gastric acid secretion havecompleted an open pilot study of continuous medication with metiamide(usually 200 mg. q.i.d. orally) for four weeks or more. Many patientshave reported complete relief or significant clinical improvement inulcer pain during metiamide therapy, often such relief occurring withinthe first few days of the start of treatment. These early reports leavelittle doubt that metiamide is effective in causing subjective relief ofulcer symptoms.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 gm. If a liquid carrier is used,the preparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg. to about 250 mg., most preferably from about100 mg. to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto four times per day. The daily dosage regimen will preferably be fromabout 150 mg. to about 1000 mg., most preferably from about 400 mg. toabout 800 mg.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the composition will be madeup in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule, injectable solutionor, when used as an anti-inflammatory agent, as a cream for topicaladministration.

The invention is illustrated but in no way limited by the followingexamples.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a five membered unsaturated heteocyclic ringhaving two nitrogen atoms and three carbon atoms, said unsaturatedheterocyclic ring being imidazole or pyrazole, and Y is oxygen orsulphur (sulphur is preferred) are exemplified by the followingexamples.

EXAMPLE 1 N-Methyl-N'-[2-(4-imidazolylmethylthio)ethyl]thiourea

i. (a) A solution of 4(5)-hydroxymethylimidazole hydrochloride (67 g.)and cysteamine hydrochloride (56.8 g.) in aqueous hydrobromic acid (1liter, 48%) was heated under reflux overnight. After cooling, thesolution was evaporated to dryness and the residual solid washed withethanol/water to give 4(5)-[(2-aminoethyl)thiomethyl]imidazoledihydrobromide (156 g.), m.p. 178°-179° .

b. Phthalimidoethanethiol (2 g.) was added portionwise with stirring toa solution of sodium ethoxide (prepared from 0.23 g. of sodium) inethanol (20 ml.) at 0° under a nitrogen atmosphere. After stirring at 0°for a further 2.5 hours, the resulting yellow solution was cooled withan ice-salt bath and a solution of 4(5)-chloromethylimidazolehydrochloride (0.76 g.) in ethanol (5 ml.) was added dropwise over 10minutes. After addition the mixture was stirred at room temperatureovernight, then acidified with ethanolic hydrogen chloride andevaporated to dryness. Addition of water precipitated unreactedphthalimidoethanethiol (0.6 g.) which was removed by filtration. Thefiltrate was concentrated and basified with aqueous sodium bicarbonatesolution to furnish a white precipitate which, on recrystallisation fromaqueous ethanol, gave 4(5)-[(2-phthalimidoethyl)thiomethyl]imidazole(0.75 g.) m.p. 136° -137° . A stirred mixture of this phthalimidoderivative (0.62 g.) in aqueous hydrobromic acid (40 ml. 18%) was heatedunder reflux overnight. After cooling to 0°, the resulting clearsolution was filtered and the filtrate evaporated to dryness.Recrystallisation of the residue from ethanol gave4(5)-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (0.52 g.), m.p.178°-179° .

c. A suspension of cysteamine hydrochloride (118.8 g.) in ethanol (200ml., dried over molecular sieves) was added portionwise at 0° to asolution of sodium ethoxide (prepared from 48 g. of sodium) in ethanol(1 liter) under a nitrogen atmosphere. After stirring at 0° , for afurther 2 hours, a solution of 4(5)-chloromethylimidazole hydrochloride(80 g.) in ethanol (400 ml.) was added dropwise over 45 minutes whilethe temperature was maintained at -1°±2° . After addition, the mixturewas stirred at room temperature overnight, filtered, and the filtrateacidified with concentrated hydrochloric acid. The solution was thenevaporated to dryness, the residue dissolved in ethanol (1 liter) and asolution of excess picric acid in hot ethanol added. The resulting crudepicrate was dissolved in water (2.7 liters) and, after decantation froman insoluble oil, the solution was left to cool to give4(5)-[(2-aminoethyl)thiomethyl]imidazole dipricate, m.p. 194°-195°.Treatment of this picrate with aqueous hydrobromic acid followed byextraction with toluene gave the dihydrobromide, m.p. 178°-179°, afterevaporation to dryness and recrystallisation of the crude residue fromethanol. (ii) A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazoledihydrobromide (10 g.) in water (25 ml.) was basified to pH 11 by theaddition of a solution of potassium carbonate (8.7 g.) in water (25ml.). The resulting solution was evaporated to dryness, extracted withisopropyl alcohol and the final traces of water removed by azeotropingwith isopropyl alcohol. The residual amine was extracted from theinorganic material with isopropyl alcohol, the extracts concentrated toabout 70 ml. and a solution of methyl isothiocyanate (2.3 g.) inisopropyl alcohol (5 ml.) added. The reaction mixture was then heatedunder reflux for 1.5 hours and, after cooling, evaporated to dryness.The residual oil was dissolved in acetone, the solution filtered toremove traces of inorganic material, and the filtrate concentrated togive N-methyl-N'-[2-(4-imidazolylmethylthio)-ethyl]thiourea (4.1 g.),m.p. 96°-98°. A sample, recrystallised from acetone, had m.p. 98°-99°.(Found: C, 41.8; H, 6.4; N, 24.4; S, 27.6. C₈ H₁₄ N₄ S₂ requires: C,41.7; H, 6.1; N, 24.3; S, 27.8).

EXAMPLE 2N-Methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea

i. (a) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride(30.0 g.) and cysteamine hydrochloride (23.0 g.) in acetic acid (200ml.) was heated under reflux for 10 hours. Following cooling to 15°-20°,the solid which crystallised was collected and washed with isopropylalcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazoledihydrochloride (45.5 g.), m.p. 189°-192°.

b. A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueoushydrochloric acid (450 ml.) was heated under reflux for 17 hours.Concentration followed by re-evaporation with water afforded a residuewhich was dissolved in isopropyl alcohol, concentrated to low bulk andcooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazoledihydrochloride (40.6 g.), m.p. 185°-191°.

c. A mixture of 4-hydroxymethyl-5-methylimidazole hydrochloride (15.0g.), cysteamine hydrochloride (11.5 g.) and a solution of hydrogenbromide in acetic acid (48%, 225 ml.) was heated under reflux for 7hours. Cooling afforded 4-methyl-5-[2-aminoethyl)thiomethyl]imidazoledihydrobromide (21.6 g.), m.p. 208°-211°.

ii. Potassium carbonate (7.75 g.) was added to a solution of4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (14.6 g.)in water (120 ml.). The solution was stored at room temperature for 15minutes and methyl isothiocyanate (5.15 g.) was added. After heatingunder reflux for 30 minutes, the solution was slowly cooled to 5°.

The product (13.1 g.) was collected and recrystallised from water togive N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea,m.p. 150°-152°. (Found: C, 44.5; H, 6.7; N, 23.0; S, 26.2. C₉ H₁₆ N₄ S₂requires: C, 44.2; H, 6.6; N, 22.9; S, 26.2).

EXAMPLES 3-13

By two-stage processes essentially similar to those described in Example1 (i) and (ii) were produced thiourea compounds of the formula:##STR14## wherein Het has the significance as set out in the followingtable I. The solvent from which the product was crystallised and themelting point and elemental analysis data of the product are also setout in the table together with the melting point of the correspondingintermediate amine salt of formula:

    Het--Ch.sub.2 SCH.sub.2 CH.sub.2 NH.sub.2.2HW

wherein W is a picrate or bromide anion as indicated in the table.

The starting materials of formula:

    Het--CH.sub.2 Q

wherein Q is hydroxyl, halogen or methoxy are all known compounds withthe exception of those used in Examples 3, 4 and 5 the preparation ofwhich is described hereinafter. In each case, the starting material wasreacted with cysteamine hydrochloride in aqueous hydrobromic acid asdescribed in Example 1 (i) (a). Where necessary, the resultant amine waspurified by conversion to the picrate followed by treatment withhydrochloric or hydrobromic acid and removal of picric acid, thusyielding the corresponding hydrochloride or hydrobromide (as describedin Example 1 (i) (c)).

Conversion of this hydrochloride or hydrobromide into the free base bythe addition of potassium carbonate followed by concentration andextraction with isopropanol or ether/ethanol (3:1) yielded an extractwhich was reacted with methyl isothiocyanate in an appropriate solventunder conditions similar to those described in Example 1 (ii). Theresultant thiourea products, where crystallisable, were recrystallisedfrom a solvent as indicated in table 1.

Preparation of starting materials for Examples 3, 4 and 5 a.5-Ethyl-4-hydroxymethylimidazole hydrochloride (Example 3)

Sulphuryl chloride (286 g.) was added dropwise to a solution of ethyl3-oxopentanoate (300 g.) in chloroform (250 ml.) at 10°-15°. Followingaddition the mixture was stirred overnight at room temperature, heatedunder reflux for 0.5 hours and cooled. After washing with water, sodiumbicarbonate and water, the solution was dried (sodium sulphate),concentrated, and fractionated to yield ethyl 2-chloro-3-oxopentanoate,b.p. 94°-96°/14 mm.

A mixture of ethyl 2-chloro-3-oxopentanoate (178 g.), freshly distilledformamide (450 g.) and water (38 ml.) was heated at 140°-148° and thencooled and added to dilute hydrochloric acid. After decanting frominsoluble material, the solution was basified with ammonium hydroxide togive a solid which, following recrystallisation from aqueous ethanol andethanol-acetate, yielded 5-ethyl-4-carbethoxyimidazole (29 g.) m.p.170°-172°. This ester (14.0 g.) was reduced with lithium aluminiumhydride (4.6 g.) in tetrahydrofuran and then treated with hydrogenchloride to give 4-ethyl-5-hydroxymethylimidazole hydrochloride (10.6g.) m.p. 141°-142° (from isopropyl alcohol-ether).

                                      TABLE 1                                     __________________________________________________________________________               Intermediate                                                                  amine salt                                                                              Product: N-methyl-N'-[2-((* * *)methylthio)ethyl]                             thiourea                                                 __________________________________________________________________________                                           Elemental Analysis                     __________________________________________________________________________    Ex.                                                                             Het           m.p. Recryst.                                                                            m.p. Molecular                                                                            Found       Required                   __________________________________________________________________________    No.                                                                             (* * * ) W    (° C)                                                                       from  (° C)                                                                       Formula                                                                              C  H  N  S  C  H  N  S                 __________________________________________________________________________     3                                                                               ##STR15##                                                                             bromide                                                                            --   aqueous ethanol                                                                     187- 189                                                                           C.sub.10 H.sub.18 N.sub.4 S.sub.2 2                                           Picrolonate                                                                          46.3                                                                             5.0                                                                              21.2                                                                             12.1                                                                             46.0                                                                             5.1                                                                              21.4                                                                             12.3               4                                                                               ##STR16##                                                                             picrate                                                                            170- 172.5                                                                         isopropyl acetate/ ether                                                            486- C.sub.11 H.sub.20 N.sub.4 S.sub.2                                                    48.5                                                                             7.6                                                                              20.8                                                                             23.6                                                                             48.5                                                                             7.4                                                                              20.6                                                                             23.5               5                                                                               ##STR17##                                                                             bromide                                                                            --   aqueous ethanol                                                                     131- 133                                                                           C.sub.15 H.sub.20 N.sub.4 S.sub.2                                                    56.0                                                                             6.2                                                                              17.3                                                                             20.0                                                                             56.2                                                                             6.3                                                                              17.5                                                                             20.0               6                                                                               ##STR18##                                                                             bromide                                                                            180- 181                                                                           aceto- nitrile                                                                      152- 153                                                                           C.sub.8 H.sub.13 BrN.sub.4 S.sub.2                                                   31.1                                                                             4.4                                                                              18.1                                                                             20.4                                                                             31.1                                                                             4.2                                                                              18.1                                                                             20.7               7                                                                               ##STR19##                                                                             bromide                                                                            181-2                                                                              water 119- 122                                                                           C.sub.9 H.sub. 16 N.sub.4 S.sub.2                                                    44.0                                                                             6.6                                                                              22.7                                                                             25.9                                                                             44.2                                                                             6.6                                                                              22.9                                                                             26.2               8                                                                               ##STR20##                                                                             bromide                                                                            196-8                                                                              methyl methyl ketone                                                                114- 115                                                                           C.sub.9 H.sub.16 N.sub.4 S.sub.2                                                     44.5                                                                             6.7                                                                              22.8                                                                             25.7                                                                             44.2                                                                             6.6                                                                              22.9                                                                             26.2               9                                                                               ##STR21##                                                                             bromide                                                                            195- 197                                                                           ethyl acetate/ petroleum ether                                                       76- 78                                                                            C.sub.8 H.sub.14 N.sub.4 S.sub.2                                                     41.8                                                                             6.1                                                                              24.3                                                                             27.9                                                                             41.7                                                                             6.1                                                                              24.3                                                                             27.8              10                                                                               ##STR22##                                                                             picrate                                                                            172- 174                                                                           isopropyl acetate/ ethanol                                                          114- 116                                                                           C.sub.9 H.sub.16 N.sub.4 S.sub.2                                                     44.5                                                                             6.8                                                                              23.0                                                                             26.2                                                                             44.2                                                                             6.6                                                                              23.0                                                                             26.2              11                                                                               ##STR23##                                                                             bromide                                                                            --   isopropyl acetate                                                                   105- 107                                                                           C.sub.10 H.sub.18 N.sub.4 S.sub.2                                                    46.4                                                                             6.8                                                                              21.6                                                                             24.8                                                                             46.5                                                                             7.0                                                                              21.7                                                                             24.8              12                                                                               ##STR24##                                                                             bromide                                                                            --   water  96- 98                                                                            C.sub.9 H.sub.15 CLN.sub.4 S.sub.2                                                   38.6                                                                             5.3                                                                              19.9                                                                             22.6                                                                             38.8                                                                             5.4                                                                              20.1                                                                             23.0              13                                                                               ##STR25##                                                                             bromide                                                                            153- 154                                                                           --    --   C.sub.8 H.sub.14 N.sub.4 S.sub.2                                                     41.9                                                                             6.1                                                                              23.7  41.7                                                                             6.1                                                                              24.3                 __________________________________________________________________________

b. 4-Isopropyl-5-hydroxymethylimidazole hydrochloride (Example 4)

A solution of sodium nitrite (43.8 g.) in water (92 ml.) was addeddropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutesat room temperature for 3 hours, water (100 ml.) was added and themixture extracted with ether. The extracts were washed with water,saturated sodium bicarbonate solution and water. After drying (CaSO₄),the solution was evaporated to give ethyl2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.

A solution of this oximinoketone (219 g.) in ethanol (280 ml.) was addedto a suspension of pre-reduced palladised charcoal (10 g., 10%) inethanol (1 lit.) and saturated ethanolic hydrogen chloride (512 ml.) andthe mixture hydrogenated at room temperature and pressure until thetheoretical amount of hydrogen was taken up. The mixture was filtered,and filtrate concentrated and ethyl acetate added to give ethyl2-amino-4-methyl-3-oxopentanoate hydrochloride (230.6 g.) m.p. 129°-131°(dec.). This aminoketone (50.5 g.) was dissolved in redistilledformamide (180 ml.) and the solution heated at 120° for 2 hours, 130°for 1 hour, and finally at 140° for 2 hours. After cooling, the mixturewas filtered and the crystalline product washed with water to give ethyl4-isopropyl-5-carbethoxy-imidazole (22 g.) m.p. 177°-178°.

This ester (108 g.) was placed in a soxhlet and reduced with lithiumaluminium hydride (34.5 g.) in tetrahydrofuran to give4-hydroxymethyl-5-isopropylimidazole (62.3 g.) m.p. 121°-123°.

c. 4-Benzyl-5-hydroxymethylimidazole hydrochloride (Example 5)

Reaction of ethyl 3-oxo-4-phenylbutyrate (10.3 g.) with sodium nitritefollowed by reduction of the crude ethyl2-oximino-3-oxo-4-phenylbutyrate (10.8 g.) as described in the previoussection, (b), gave ethyl 2-amino-3-oxo-4-phenylbutyrate hydrochloride(8.5 g.) m.p. 150°-153°. An analytical sample, recrystallised fromethanol/ethyl acetate, had m.p. 154°-155°.

Reaction of this aminoketone (160 g.) with formamide (480 ml.) by themethod described in the previous section, (b), gave4-benzyl-5-carbethoxyimidazole (75 g.) m.p. 168.5°-169.5°. Reduction ofthis ester (30 g.) with lithium aluminium hydride (6.4 g.) intetrahydrofuran (600 ml.), followed by addition of water, filtration andacidification of the filtrate with ethanolic hydrogen chloride, gave4-benzyl-5-hydroxymethylimidazole hydrochloride (22.9 g.), m.p.149°-151°, after concentration and addition of ethyl acetate.

EXAMPLES 14-16

Two stage processes as described in Examples 3-13 were used for theproduction of compounds of the following formula: ##STR26## wherein R₁has the significance as set out in Table 2. In each case theintermediate amine was of the formula: ##STR27##

                                      TABLE 2                                     __________________________________________________________________________    Product: N-(* * *)-N'-(ω-(4-imidazolylmethylthio)* *)thiourea                     Recrystal-        Elemental Analysis                                Ex.       lised m.p. Molecular                                                                            Found       Required    Nomenclature              __________________________________________________________________________    No.                                                                              m R.sub.1                                                                            from  (° C)                                                                       Formula                                                                              C  H  N  S  C  H  N  S  ***  ω                                                                         ***                __________________________________________________________________________    14 3 CH.sub.3                                                                           water 118- C.sub.9 H.sub.16 N.sub.4 S.sub.2                                                     44.0                                                                             6.7                                                                              22.9                                                                             25.7                                                                             44.2                                                                             6.6                                                                              22.9                                                                             26.2                                                                             methyl                                                                             3 propyl                             120                                                           15 2 C.sub.2 H.sub.5                                                                    water 128- C.sub.9 H.sub.16 N.sub.4 S.sub.2                                                     44.2                                                                             6.9                                                                              23.2                                                                             26.4                                                                             44.2                                                                             6.6                                                                              22.9                                                                             26.2                                                                             ethyl                                                                              2 ethyl                              129                                                           16 2 CH.sub.2 CH.sub.2 -                                                                isopropyl                                                                           97-  C.sub.11 H.sub.21 N.sub.5 S.sub.2                                                    46.2                                                                             7.6                                                                              24.7                                                                             22.2                                                                             46.0                                                                             7.4                                                                              24.4                                                                             22.3                                                                             2-di-                                                                              2 ethyl                   N(CH.sub.3).sub.2                                                                  acetate/                                                                            99.5                                methyl-                             ether                                     amino-                                                                        ethyl                     __________________________________________________________________________     Table 2 shows the values for m and R.sub.1 and recrystallisation solvent,     melting point and elemental analysis for each product.

Using the process of Example 14 from 4-methyl-5-[(3-aminopropyl)thiomethyl]imidazole dihydrobromide, m.p. 200.5°-202.5°, the product isN-methyl-N'-[3-((4-methyl-5 -imidazolyl)methylthio)propyl]thiourea, m.p.104.5°-105.5° (from methyl ethyl ketone). (Found: C, 46.6; H, 7.0; N,21.7; S, 24.6. C₁₀ H₁₈ N₄ S₂ requires: C, 46.5; H, 7.0; N, 21.7; S,24.8).

Using the process of Example 15, commencing from4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole, the product isN-ethyl-N'-[2-(4-methyl-5 -imidazolyl)methylthio)ethyl]-thiourea, m.p.140°-141°. (Found: C, 46.5; H; 7.1; N, 21.7; S, 25.1. C₁₀ H₁₈ N₄ S₂requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).

EXAMPLE 17

N-Methyl-N'-[2-(2-(4-imidazolyl)ethyl)thioethyl]thiourea dihydroiodide

i. A solution of 4(5)-(2-chloroethyl)imidazole hydrochloride (13.6 g.)and cysteamine hydrochloride (9.3 g.) in distilled water (100 ml.) wasadded over 30 minutes to a stirred solution of potassium hydroxide (15.8g., 85%) in water (40 ml.) at room temperature under a nitrogenatmosphere. After addition the solution was heated for 4 hours at 50°.From time to time it was necessary to add a few drops of potassiumhydroxide solution to prevent the pH of the reaction mixture fallingbelow 11. The reaction mixture was then acidified with 2N hydrochloricacid, evaporated to dryness under reduced pressure and the final tracesof water removed by azeotroping with n-propanol. The residue wasextracted several times with isopropyl alcohol and the combined extractsadded to a hot solution of picric acid in isopropyl alcohol. On cooling,this gave 4(5)-[2-(2-aminoethyl)thioethyl] imidazole dipicrate (42.3 g.)m.p. 225°-226°.

ii. This dipicrate was converted to the dihydrochloride by addition ofconcentrated hydrochloric acid (200 ml.) followed by extraction withtoluene (5×50 ml.). The aqueous solution was evaporated to dryness, theresidue dissolved in water and the solution basified by the addition ofaqueous potassium carbonate solution. This mixture was then evaporatedto dryness and the residue extracted with n-propanol to give the crudebase of 4(5)-[2-(2-aminoethyl)-thioethyl]imidazole on removal of then-propanol. A solution of this base (3.3 g.) and methyl isothiocyanate(1.9 g.) in ethanol (15 ml.) was heated under reflux for 30 minutes.After cooling the solution was evaporated to dryness and the residuechromatographed on silica gel. Elution with ethyl acetate/methanol (3:2)and evaporation of the appropriate middle fractions gave an oilyresidue, which was acidified with aqueous hydriodic acid (64%).Decantation several times with ether gave a yellow precipitate which, onwashing with acetonitrile and then ether, gaveN-methyl-N'-[2-(2-(4-imidazolyl) ethyl)thioethyl] thiourea hydroiodide,m.p. 143°-145°, as an off-white solid. (Found: C, 21.6; H, 3.7; N, 11.1;S, 12.9; I, 50.7. C₉ H₁₆ N₄ S₂.2HI requires: C, 21.6; H, 3.6; N, 11.2;S, 12.8; I, 50.7).

EXAMPLE 18 N-[2-(4-Imidazolylmethylthio)ethyl]thiourea

i. A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazole (6.0 g.) andbenzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) was heated underreflux for one hour. Concentration followed by recrystallisation fromethyl acetate-isopropyl acetate affordedN-benzoyl-N'-[2-(4-imidazolylmethylthio)-ethyl] thiourea (7.5 g.). Ananalytically pure sample (from aqueous isopropyl alcohol) has m.p.126°-128°.

(ii) The benzoyl thiourea (6.0 g.) was added to a solution of potassiumcarbonate (1.4 g.) in water (80 ml.), at 60°. The solution wasmaintained at this temperature for one hour, concentrated to low bulkand acidified with hydrochloric acid. Benzoic acid was removed byfiltration and the filtrate was basified with potassium carbonate andconcentrated under reduced pressure. Following extraction with isopropylalcohol and concentration, the product was crystallised from isopropylacetate. Recrystallisation from water gaveN-[2-(4-imidazolymethylthio)ethyl]thiourea (2.5 g.) m.p. 135°-137°.(Found C, 38.9; H, 5.5; N, 26.1; S, 29.6. C₇ H₁₂ N₄ S₂ requires: C,38.9; H, 5.6; N; 25.9; S, 29.6).

EXAMPLE 19 N-[(2-(4-methyl-5-imidazoylyl)methylthio)ethyl]thiourea

a. The reaction of 4-methyl-5-((2-amino ethyl)thiomethyl)-imidazole (5.0g.) and benzoyl isothiocyanate (23.8 g.) by the procedure described inExample 18 (i) affordedN-benzoyl-N'-[(2-(4-methyl-5-imidazolyl)methylthio)ethyl] thiourea (24g.), m.p. 138°-140° (from isopropyl alcohol-ethylacetate-ether). Ananalytically pure sample obtained by recrystallisation from aqueousisopropyl alcohol had m.p. 165°-166°.

b. The crude benzoyl thiourea (22 g.) was hydrolysed with potassiumcarbonate by the procedure described in Example 18 (ii) to affordN-[2-(4-methyl-5-imidazolyl)methylthio)ethyl]-thiourea (7.5 g.). Furtherrecrystallisation from water, followed by isopropyl alcohol-ether gavethe pure product (3.8 g.) m.p. 110°-112°. (Found: C, 41.9; H, 6.3; N,24.5; S, 28.0 C₈ H₁₄ N₄ S₂ requires: C, 41.7; H, 6.1; N, 24.3; S, 27.8).

EXAMPLE 20 4,5-bis-[2-(N-Methylthioureido)ethylthiomethyl]imidazole

i. The reaction of 4,5-di(hydroxymethyl)imidazole hydrochloride (1.6 g.)with cysteamine hydrochloride (2.2 g.) by the procedure described inExample 1 (i) (a) afforded 4,5-bis-((2-aminoethyl)thiomethyl)imidazoletrihydrobromide (3.8 g.), m.p. 233°-236°.

ii. The reaction of 4,5-bis-((2-aminoethyl)thiomethyl)-imidazole (1.2g.) with methyl isothiocyanate (1.5 g.) by the procedure described inExample 1 (ii) afforded4,5-bis-[2-(N-methylthioureido)ethylthiomethyl]imidazole (1.1 g.) m.p.154°-155° (from isopropyl alcohol - isopropyl acetate) (Found: C, 39.8;H, 6.2; N, 21.5; S, 32.5. C₁₃ H₂₄ N₆ S₄ requires: C, 39.8; H, 6.2; N,21.4; S, 32.7).

EXAMPLE 21 N-Methyl-N'-[3-(2-imidazolythio)propyl]thiourea

i. A solution of 2-mercaptoimidazole (2 g.) and 3-aminopropanol (1.14ml.) in hydrobromic acid (48%, 25 ml.) was heated under reflux for 25hours. The reaction mixture was evaporated to dryness and the oilyresidual solid recystallised twice from ethanol/ether to give2-(3-aminopropyl-mercapto)imidazole dihydrobromide (3.55 g.) m.p.160°-162°.

(ii) This amine dihydrobromide (7 g.) was converted to the free base andreacted with methyl isothiocyanate (1.75 g.), by the method described inExample 1 (ii), to give a crude yellow solid after evaporation of thereaction mixture. This crude product was washed with acetone/isopropylacetate (1:1) and recrystallised from water to giveN-methyl-N'-[3-(2-imidazolylthio)propyl] thiourea (3.46 g.) m.p.139°-141°. (Found: C, 41.5; H, 6.1; N, 24.1; S, 27.7. C₈ H₁₄ N₄ S₂requires: C, 41.7; H, 6.1; N, 24.3; S, 27.8).

EXAMPLE 22

The process described in Example 21 (i) was used to prepare2-(3-aminopropylthio)-1-methylimidazole dihydrobromide, m.p. 164°-166°.

This amine dihydrobromide was used in the process of Example 21 (ii) togive a product which was crystallised from water to giveN-methyl-N'-[(3-(1-methyl-2-imidazolyl)-thio)propyl]thiourea, m.p.109°-111°. (Found: C, 44.5; H, 6.5; N, 23.1; S, 26.3. C₉ H₁₆ N₄ S₂requires: C, 44.2; H, 6.6; N, 22.9; S, 26.2).

EXAMPLE 23 N-Methyl-N'-[2-(4-imidazolymethoxy)ethyl]thiourea

i. A stirred suspension of 4-(2-chloroethoxymethyl)imidazolehydrochloride (14.7 g.) and sodium azide (9.8 g.) in drydimethylformamide (103 ml.) was maintained at 95° for 5 hours and thenset aside overnight at room temperature. Following dilution with waterand filtration, the filtrate was concentrated and the residue purifiedby chromatography on a dry column of alumina using ethanol. The productwas basified with potassium carbonate (6.5 g.) in water (3 ml.) and theanhydrous residue was extracted with isopropyl alcohol (3 × 50 ml.).Concentartion of the extracts afforded 4-(2-azidoethoxymethyl)imidazole(7.2 g.). Hydrogenation of the azido compound (7.2 g.) in isopropylalcohol (142 ml.) over platinum oxide catalyst (3.0 g.) gave4-(2-aminoethoxymethyl) imidazole (6.48 g.). A sample of the monopicratemonohydrochloride had m.p. 139°-140° (from nitromethane). (Found: C,35.4; H, 3.8; N, 20.5; Cl, 8.8. C₁₂ H₁₅ ClN₆ O₈ requires: C, 35.4; H,3.7; N, 20.7; Cl, 8.7).

ii. 4-(2-Aminoethoxymethyl)imidazole (2.24 g.) was caused to react withmethyl isothiocyanate (1.21 g.) in isopropyl alcohol (25 ml.) in theusual way. The crude product was purified by chromatography on a columnof silica gel with ethyl acetate as eluant and subsequently on a drycolumn of alumina, using chloroform. The final product wasrecrystallised from ethyl acetate to giveN-methyl-N'-[2-(4-imidazolylmethoxy)ethyl] thiourea (0.80 g.), m.p.96°-98°. (Found: C, 44.6; H, 6.5; N, 26.0; S, 14.7. C₈ H₁₄ N₄ OSrequires: C, 44.8; H, 6.6; N, 26.2; S, 15.0).

EXAMPLE 24 N-Methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]urea

A mixture of 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole (5.1 g.)and methyl isocyanate (2.0 g.) in acetonitrile was heated for 18 hoursin a pressure vessel at 100°. After cooling, the solid obtained wascollected and recrystallised from isopropyl alcohol-acetonitrile to giveN-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl] urea (4.0 g.)m.p. 158°-159°. (Found: C, 47.4; H, 7.1; N, 24.5; S, 14.1. C₉ H₁₆ N₄ OSrequires: C, 47.3; H, 7.1; N, 24.5; S, 14.0).

EXAMPLE 25N-Methyl-N'-[2-(1,4-dimethyl-2-imidazolyl)methylthio)ethyl]-thiourea

i. The reaction of 1,4-dimethylimidazole (5.65 g.) with n-butyl lithiumfollowed by treatment with formaldehyde according to the methoddescribed for the preparation of3-hydroxymethyl-5,6,7,8-tetrahydroimidazol[1,5-a]pyridine (used forExample 224) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p.125°-126° (ethyl acetate-petroleum ether).

ii. The reaction of 1,4-dimethyl-2-hydroxymethylimidazole (2.5 g.) withcysteamine hydrochloride (2.5 g.) in aqueous hydrobromic acid by themethod described in Example 1 (i) (a) gave1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide (6.2g.) m.p. 161°-163° (from isopropyl alcohol-methoanol).

iii. The reaction of 1,4-dimethyl-2-[(2-aminoethyl)thiomethyl]imidazole(derived from the 6.2 g. dihydrobromide) with methyl isothiocyanate(1.34 g.) in ethanol (50 ml.) followed by chromatography on a column ofsilica gel with ethyl acette-ethanol (9:1) as eluant gaveN-methyl-N'-[2-(1,4-dimethyl-2-imidazolyl)methylthio)ethyl]thiourea (2.1g.). (Found: C, 4.8; H, 6.9; N, 21.5; S, 24.9. C₁₀ H₁₈ N₄ S₂ requires:C, 46.5; H, 7.0; N, 21.7; S, 24.8).

EXAMPLE 26N-Methyl-N'-[2-((4-trifluoromethyl-5-imidazolyl)methylthio)-ethyl]thiourea

A mixture of ethyl 2-chloro-4,4,4-trifluoroacetate (65.7 g.), distilledformamide (135 g.) and water (11 ml.) was heated at 129°-130° for 1.5hours. After cooling, an equal volume of ice-cold water was added togive 4-trifluoromethyl-5-carbethoxyimidazole, m.p. 184°-186° (fromaqueous methanol).

Reduction of the ester (9.4 g.) with lithium aluminium hydride (2.4 g.)in tetrahydrofuran gave 5-hydroxymethyl-4-trifluoromethylimidazole,isolated as its picrate, m.p. 135.5°-137.5° (from aqueous isopropylalcohol).

The picrate (5.3 g.) was dissolved in 48% aqueous hydrobromic acid andextracted with toluene to remove picric acid. Cysteamine hydrochloride(1.52 g.) was added to the aqueous phase and the acidic solution heatedunder reflux for 12 hours. Concentration and trituration of the residuewith ethanol-ether gave4-trifluoromethyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrobromide(3.2 g.), m.p. 179°-182°. Basification followed by treatment with methylisothiocyanate gaveN-methyl-N'-[2-((4-trifluoromethyl-5-imidazolyl)methylthio)ethyl]thiourea.

EXAMPLE 27 N-[(2-(4-methyl-5-imidazolyl)methylthio)ethyl]urea

A solution of 4-methyl-5-[(2-amino-ethyl)thiomethyl]imidazoledihydrobromide (3.33 g.), potassium cyanate (0.81 g.) and potassiumcarbonate (0.69 g.) in water (30 ml.) was heated at 80°-90° for 3 hours.Concentration under reduced pressure and extraction of the residue withn-propanol gave the crude product which was chromatographed on a columnof silica gel with ethyl acetate-ethanol (5:1) as eluant.Recrystallisation from isopropyl alcohol-ether and finally fromacetonitrile furnishedN-[(2-(4-methyl-5-imidazolyl)methylthio)ethyl]urea (0.8 g.), m.p.148°-149°. (Found: C, 44.6; H, 6.5; N, 25.7; S, 15.0. C₈ H₁₄ N₄ OSrequires: C, 44.8; H, 6.6; N, 26.1; S, 15.0).

EXAMPLE 28 N-Methyl-N'-[3-(4-imidazolylmethoxy)propyl]thiourea

i. Sodium (13.5 g.) was added over 3 hours to propane-1,3-diol (450 ml.)under nitrogen at 70° with stirring. This solution was added over 20minutes to a stirred solution of 4-chloromethylimidazole hydrochloride(50.0 g.) under nitrogen at 40°-60°. Subsequent heating at 60°-65° for 3hours followed by overnight cooling, filtration and concentration gave4-(3-hydroxypropoxy)methylimidazole. Subsequent reaction with thionylchloride gave 4-(3-chloropropoxy)methylimidazole hydrochloride (38.8g.).

ii. The reaction of this chloride (36.2 g.) with sodium azide (22.4 g.)in dry dimethylformamide at 90° for 3 hours followed by `dry-column`chromatography on aluminium with ethanol as eluant gave4-(3-azidopropoxy)methylimidazole which was further purified by the samemethod using chloroform as eluant. The azide (2.95 g.) in ethanol (200ml.) was hydrogenated over platinum oxide catalyst to give4-(3-aminopropoxy)methylimidazole (2.42 g.).

iii. Reaction of the amine (2.42 g.) with methyl isothiocyanate (1.25g.) in ethanol at room temperature for 65 hours followed bychromtography of the product on a column of silica gel with ethylacetate as eluant gaveN-methyl-N'-[3-(4-imidazolylmethoxy)propyl]thiourea (0.49 g.) as a lowmelting solid.

EXAMPLE 29N-Methyl-N'-[2-((2-amino-4-imidazolyl)methylthio)ethyl]thiourea

Freshly prepared sodium amalgam (90 g.) is added over 75 minutes to astirred solution of series ethyl ester dihydrochloride (3.0 g.) inwater/ethanol (2:1), the temperature being maintained within the rangeof from -12° to -10° and the pH at about 2.5 by the addition of 5Nhydrochloric acid. After a further 45 minutes the mixture is allowed towarm to 10° and the precipitated free mercury is removed. Canamide isadded and the mixture warmed to 50° for 30 minutes, left at 0° for 18hours and evaporated to dryness. After washing with ether to remove anyunchanged cyanamide, the residue is extracted with hot ethanol andheated with hot ethanolic picric acid. Concentration and cooling of thesolution gives 2-amino-4-hydroxymethylimidazole picrate.

Reaction of 2-amino-4-hydroxymethylimidazole hydrochloride (which isobtained by treating the picrate salt with hydrochloric acid) withcysteamine hydrochloride and reaction of the resulting2-amino-4-[(2-aminoethyl)-thiomethyl]imidazole with methylisothiocyanate by the methods of Example 1 givesN-methyl-N'-[2-((2-amino-4-imidazolyl)methylthio)ethyl]thiourea.

EXAMPLE 30

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-((5-methyl-4-imidazolyl)-                                      methylthio)ethyl]thiourea  150 mg.                                            Sucrose                    75 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 31

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(4-imidazolylmethylthio)-                                      ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 32

By the procedure of Example 1, using in place of4(5)-hydroxymethylimidazole hydrochloride, the hydrochloride salts ofthe following compounds:

5-methyl-3-hydroxymethylpyrazole

3,5-dimethyl-4-hydroxymethylpyrazole

5-hydroxy-3-hydroxymethylpyrazole

3,4-di(hydroxymethyl)pyrazole

the following products are obtained, respectively:

N-methyl-N'-[2-((5-methyl-3-pyrazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((3,5-dimethyl-4-pyrazolyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-((5-hydroxy-3-pyrazolyl)methylthio)ethyl]-thiourea

3,4-bis-[2-(N-methylthioureido)ethylthiomethyl]pyrazole.

EXAMPLE 33N-Methyl-N'-[2-((4-hydroxy-3-pyrazolyl)methylthio)ethyl]thiourea

4-Hydroxy-3-pyrazolecarboxylic acid is converted to the ethyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofuranto give 4-hydroxy-3-hydroxymethylpyrazole, which is treated with aqueoushydrochloric acid to give the hydrochloride salt.

Using 4-hydroxy-3-hydroxymethlpyrazole hydrochloride in place of4(5)-hydroxymethylimidazole hydrochloride in the procedure of Example 1gives the title compound.

EXAMPLE 34

By the procedure of Example 17, 3-(2-chloroethyl)-pyrazole (which isprepared by treating 3-(2-hydroxyethyl)-pyrazole with thionyl chloride)is reacted with cysteamine hydrochloride in the presence of aqueouspotassium hydroxide to give 3-[2-(2-aminoethyl)thioethyl]pyrazoledipicrate which is converted to the dihydrochloride salt and then to thebase and reacted with methyl isothiocyanate to giveN-methyl-N'-[2-(2-(3-pyrazolyl)ethyl)thioethyl]thiourea.

Using ethyl isothiocyanate in place of methyl isothiocyanate, thecorresponding N-ethyl compound is obtained.

Also, by the procedure of Example 1, using 3-hydroxymethylpyrazole and3-mercaptopropylamine as the starting materials,N-methyl-N'-[3-(3-pyrazolylmethylthio)-propyl]thiourea is prepared.

EXAMPLE 35 N-Methyl-N'-[2-(3-pyrazolylmethylthio)ethyl]urea

By the procedure of Example 24, 3-[(2-aminoethyl)-thiomethyl]pyrazole isreacted with methyl isocyanate to give the title compound.

EXAMPLE 36

By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]pyrazole isreacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(3-pyrazolylmethylthio)ethyl]thiourea. Removing thebenzoyl group by the procedure of Example 18 givesN-[2-(3-pyrazolylmethylthio)ethyl]thiourea.

EXAMPLE 37N-(2-Dimethylaminoethyl)-N'-[2-(3-pyrazolylmethylthio)ethyl]-thiourea

Treatment of 3-[(2-aminoethyl)thiomethyl]pyrazole with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 38 N-Methyl-N'-[2-(3-pyrazolylmethoxy)ethyl]thiourea

3-Chloromethylpyrazole, prepared by racting 3-hydroxymethylpyrazole withthionyl chloride, is reacted with the sodium salt of ethylene glycol togive 3-(2-hydroxyethoxymethyl)-pyrazole. Treatment of3-(2-hydroxyethoxymethyl)pyrazole with thionyl chloride gives3-(2-chloroethoxymethyl)pyrazole.

Using 3-(2-chloroethoxymethyl)pyrazole hydrochloride (prepared from thebase by treating with hydrochloric acid) in the procedure of Example 23gives N-methyl-N'-[2-(3-pyrazolylmethoxy)ethyl]thiourea.

EXAMPLE 39

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-pyrazolylmethylthio)-                                       ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a five membered unsaturated heterocyclic ringhaving two nitrogen atoms and three carbon atoms, said unsaturatedheterocyclic ring being imidazole or pyrazole, and Y is NH areexemplified by the following examples.

EXAMPLE 40 N-Methyl-N'-[2-(4(5)-imidazolylmethylamino)ethyl]thiourea

a. (i) 4(5)-Chloromethylimidazole (1.16 g., 0.01 m.) in 10 ml. ofethanol is added slowly to excess ethylenediamine (6.0 g.) in 25 ml. ofethanol. The mixture is heated at 55° for 1 hour, then concentratedunder reduced pressure and basified with sodium hydroxide. Evaporationunder high vacuo and steam distillation followed by concentration todryness, extraction with ethanol and acidification with ethanolichydrogen chloride gives N-(4(5)-imidazolylmethyl)-ethylenediamine. (ii)Methyl isothiocyanate (0.73 g.) is added slowly to a solution of 1.4 g.of N-(4(5)-imidazolylmethyl)ethylenediamine in 20 ml. of ethanol. Themixture is heated under reflux for 30 minutes, then concentrated and theresidue separated by column chromatography to give the title compound.(b) Sodium hydride (54% suspension in mineral oil, 4.5 g.) is added to asolution of 15.6 g. of N-trifluoroacetyl-ethylenediamine in drydimethylformamide under a nitrogen atmosphere.4(5)-Chloromethylimidazole (11.6 g.) is added slowly and the mixture isallowed to stand overnight at room temperature. The solvent is removedunder reduced pressure and the residue dissolved in a small volume ofwater and extracted with chloroform. The extracts are dried overanhydrous sodium sulphate, filtered and 7.3 g. of methyl isothiocyanateis added. The mixture is heated at reflux for 30 minutes, thenconcentrated under reduced pressure, treated with aqueous hydrogenchloride and basified with aqueous potassium carbonate to give the titlecompound. (c) A mixture ofN-formyl-N-(4(5)-imidazolylmethyl)ethylenediamine (prepared by addingsodium hydride to N-formylethylenediamine in dry dimethylformamide, thenreacting with 4(5)-chloromethylimidazole at room temperature) and methylisothiocyanate is heated under reflux for 30 minutes, then concentrated.Treating with aqueous hydrogen chloride, then basifying with aqueouspotassium carbonate gives the title compound.

EXAMPLE 41

Using, in the procedure of Example 40, in place of4(5)-chloromethylimidazole the following compounds (which may beprepared from the corresponding hydroxymethylimidazoles by treatmentwith thionyl chloride):

4-chloromethyl-5-methylimidazole

4-chloromethyl-5-ethylimidazole

4-chloromethyl-5-isopropylimidazole

4-chloromethyl-5-benzylimidazole

4-chloromethyl-5-bromoimidazole

4-chloromethyl-2-methylimidazole

4-chloromethyl-1-methylimidazole

2-chloromethylimidazole

2-chloromethyl-1,5-dimethylimidazole

5-chloro-2-chloromethyl-1-methylimidazole

the products are, respectively:

N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-ethyl-4-imidazolyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-((5-isopropyl-4-imidazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-benzyl-4-imidazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-bromo-4-imidazolyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-((2-methyl-4-imidazolyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-((1-methyl-4-imidazolyl)methylamino)ethyl]-thiourea

N-methyl-N' -[2-(2-imidazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((1,5-dimethyl-2-imidazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-chloro-1-methyl-2-imidazolyl)methylamino)ethyl]thiourea.

The corresponding N-ethyl compounds are prepared using ethylisothiocyanate in place of methyl isothiocyanate.

EXAMPLE 42

Using 5-chloromethyl-4-trifluoromethylimidazole (prepared by reactingthe corresponding 5-hydroxymethyl compound with thionyl chloride) in theprocedure of Example 40 givesN-methyl-N'-[2-((4-trifluoromethyl-5-imidazolyl)methylamino)ethyl]thiourea

Also, using 2-amino-4-chloromethylimidazole in the procedure of Example40 givesN-methyl-N'-[2-((2-amino-4-imidazolyl)methylamino)ethyl]thiourea.

Reacting N-(4(5)-imidazolylmethyl)ethylenediamine with methyl isocyanateby the procedure of Example 24, then concentrating and separating theresidue by column chromatography givesN-methyl-N'-[2-(4(5)-imidazolylmethylamino)ethyl]urea.

Using 4(5)-chloromethylimidazole and 1,3-diamino-propane as startingmaterials in the procedure of Example 40 givesN-methyl-N'-[3-(4(5)-imidazolylmethylamino)propyl]-thiourea.

EXAMPLE 43 N-Methyl-N'-[2-(2-(4(5)-imidazolyl)ethylamino)ethyl]thiourea

By the procedure of Example 40 using 4(5)-(2-chloroethyl)imidazole, theproduct is N-methyl-N'-[2-(2-(4(5)-imidazolyl)ethylamino)ethyl]thiourea.

EXAMPLE 44 4,5-bis-[2-(N-Methylthioureido)ethylaminomethyl]imidazole

Using 4,5-di(chloromethyl)imidazole in the procedure of Example 40 givesthe title compound.

EXAMPLE 45 N-Methyl-N'-[2-((5-methyl-4-imidazolyl)methylamino)ethyl]urea

By the procedure of Example 24,N-(5-methyl-4-imidazolylmethyl)ethylenediamine is reacted with methylisocyanate to give, after concentrating and separating the residue bycolumn chromatography, the title compound.

EXAMPLE 46 N-[2-(4(5)-Imidazolylmethylamino)ethyl]thiourea

A mixture of 6.0 g. of N-(4(5)-imidazolylmethyl)-ethylenediamine and 6.0g. of benzoyl isothiocyanate in 150 ml. of chloroform is heated underreflux for one hour, then concentrated and chromatographed to giveN-benzoyl-N'-[2-(4(5)-imidazolylmethylamino)ethyl]thiourea.

The benzoyl thiourea is added to a solution of potassium carbonate inwater at 60° C. The mixture is maintained at this temperature for onehour, then concentrated and acidified with hydrochloric acid. Themixture is filtered and the filtrate is basified with potassiumcarbonate, concentrated and extracted with isopropyl alcohol. Theextract is concentrated to giveN-[2-(4(5)-imidazolylmethylamino)ethyl]thiourea.

EXAMPLE 47N-(2-Dimethylaminoethyl)-N'-[2-(4(5)-imidazolylmethylamino)-ethyl]thiourea

Treating N-(4(5)-imidazolylmethyl)ethylenediamine with2-dimethylaminoethyl isothiocyanate, then concentrating and separatingby column chromatography by the procedure of Example 40(a)(ii) givesN-(2-dimethylaminoethyl)-N'-[2-(4(5)-imidazolylmethyl)amino)ethyl]thiourea.

EXAMPLE 48

Treating the product of Example 40 with hydrochloric acid givesN-methyl-N'-[2-(4(5)-imidazolylmethylamino)ethyl]-thioureahydrochloride.

TreatingN-methyl-N'-[2((5-methyl-4-imidazolyl)-methylamino)ethyl]thiourea withmaleic acid in ethanol gives the maleate salt.

EXAMPLE 49

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(4(5)-imidazolylmethylamino)-                                  ethyl]thiourea             200 mg.                                            Sucrose                    75 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 50

    ______________________________________                                        Ingredients                 Amounts                                           ______________________________________                                        N-Methyl-N'-[2-((5-methyl-4-imidazolyl)methyl)-                               amino)ethyl]thiourea        150 mg.                                           Lactose                     100 mg.                                           ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 51

Using, in the procedure of Example 40, the followingbromomethylpyrazoles (which may be prepared by treating thehydroxymethylpyrazoles with thionyl bromide):

3-bromomethylpyrazole

5-methyl-3-bromomethylpyrazole

3,5-dimethyl-4-bromomethylpyrazole

5-hydroxy-3-bromomethylpyrazole

3,4-di(bromomethyl)pyrazole

the products are, respectively:

N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((5-methyl-3-pyrazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3,5-dimethyl-4-pyrazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-hydroxy-3-pyrazolyl)methylamino)-ethyl]thiourea

3,4-bis-[2-(N-methylthioureido)ethylaminomethyl]pyrazole.

Similarly, using 3-(2-bromoethyl)pyrazole in the procedure of Example40, the product isN-methyl-N'-[2-(2-(3-pyrazolyl)ethylamino)ethyl]thiourea.

Also, in the procedure of Example 40, using 3-bromomethylpyrazole and1,3-diaminopropane, the product isN-methyl-N'-[3-(3-pyrazolylmethylamino)propyl]thiourea.

Using ethyl isothiocyanate in place of methyl isothiocyanate thecorresponding N-ethyl compounds are prepared.

EXAMPLE 52N-Methyl-N'-[2-((4-hydroxy-3-pyrazolyl)methylamino)ethyl]-thiourea

4-Hydroxy-3-hydroxymethylpyrazole (which is prepared by converting4-hydroxy-3-pyrazolecarboxylic acid to its ethyl ester and reducing theester with lithium aluminium hydride) is treated with thionyl bromide atroom temperature to give 3-bromomethyl-4-hydroxypyrazole.

Using 3-bromomethyl-4-hydroxypyrazole in the procedure of Example 40gives the title compound.

EXAMPLE 53

The reaction of 8.3 g. (0.1 m.) of 3-aminopyrazole and 13.3 g. (0.1 m.)of β-azidopropionyl chloride in pyridine gives3-(β-azidopropionamido)pyrazole. Reduction of this compound withdiborane in ethylene glycol/dimethyl ether yields3-(3-aminopropylamino)pyrazole.

A mixture of 2.55 g. of 3-(3-aminopropylamino)-pyrazole and 1.46 g. ofmethyl isothiocyanate in 50 ml. of isopropyl alcohol is stirred at roomtemperature for 16 hours to give, after concentrating and trituratingthe residue under methyl ethyl ketone,N-methyl-N'-[3-(3-pyrazolylamino)propyl]thiourea.

By the same procedure, starting from 2-aminoimidazole,N-methyl-N'-[3(2-imidazolylamino)propyl]thiourea is prepared.

EXAMPLE 54

By the procedure of Example 46, reacting 3-(3-aminopropylamino)pyrazole(prepared as in Example 53) with benzoyl isothiocyanate givesN-benzoyl-N'-[3-(3-pyrazolylamino)propyl]thiourea.

Treating the benzoyl thiourea with potassium carbonate by the procedureof Example 46 gives N-[3-(3-pyrazolylamino)propyl]thiourea.

EXAMPLES 55N-(2-Dimethylaminoethyl)-N'-[2-(3-pyrazolylmethylamino)ethyl]-thiourea

Treating N-(3-pyrazolylmethyl)ethylenediamine with 2-dimethylaminoethylisothiocyanate by the procedure of Example 40 gives the title compound.

EXAMPLE 56 N-Methyl=N'-[2-(3-pyrazolylmethylamino)ethyl]urea

N-(3-Pyrazolylmethyl)ethylenediamine is reacted with methyl isocyanateby the procedure of Example 24 to give, after concentrating andseparating the residue by column chromatography, the title compound.

EXAMPLE 57

Treating N-[3-(3-pyrazolylamino)propyl]thiourea with maleic acid inethanol gives the maleate salt.

Treating N-methyl-N'-[2-(3-pyrazolylmethylamino)-ethyl]thiourea withhydrobromic acid gives the hydrobromide salt.

EXAMPLE 58

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-pyrazolylmethylamino)-                                      ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a six membered unsaturated heterocyclic ringhaving two nitrogen atoms and four carbon atoms, said unsaturatedheterocyclic ring being pyrimidine, pyrazine or pyridazine, and Y isoxygen or sulphur (sulphur is preferred) are exemplified by thefollowing examples.

EXAMPLES 59 N-Methyl-N'-[2-(2-pyrimidylmethylthioethyl]thiourea

A mixture of 5-bromo-2-hydroxymethylpyrimidine (5.6 g.) and magnesiumoxide (5.6 g.) in water/ethanol (2:1) was submitted to hydrogenolysisover 10% palladised charcoal for 0.5 hours. Filtration, concentrationand ether extraction from an aqueous solution of the residue afforded2-hydroxymethylpyrimidine (1.85 g.) as a mobile liquid.

The reaction of 2-chloromethylpyrimidine (prepared from thehydroxymethyl compound by reaction thereof with thionyl chloride) withphthalimidoethanethiol, hydrazinolysis to remove the protectingphthalimido group and reaction of the product with methylisothiocyanate, according to the method described in Example 1, gaveN-methyl-N'-[2-(2-pyrimidylmethylthio)ethyl]thiourea.

EXAMPLE 60

Using the following chloromethylpyrimidine compounds (prepared wherenecessary from the corresponding hydroxymethyl compounds and thionylchloride) in the procedure of Example 50:

4-chloromethyl-6-methylpyrimidine

2-chloromethyl-5-methylpyrimidine

4-hydroxy-2-chloromethylpyrimidine

5-bromo-2-chloromethylpyrimidine

2-chloro-4-chloromethylpyrimidine

2-amino-4-chloromethylpyrimidine

5-chloromethyl-2,4-dimethylpyrimidine

4-chloro-2-methyl-5-chloromethylpyrimidine

the products are, respectively:

N-methyl-N'-[2-((6-methyl-4-pyrimidyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((5-methyl-2-pyrimidyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((4-hydroxy-2-pyrimidyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-((5-bromo-2-pyrimidyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((2-chloro-4-pyrimidyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-((2-amino4-pyrimidyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-((2,4-dimethyl-5-pyrimidyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-((4-chloro-2-methyl-5-pyrimidyl)methlthio)-ethyl]thiourea.

The corresponding N-ethyl compounds are prepared using ethylisothiocyanate in place of methyl isothiocyanate.

In the procedure of Example 1(i)(b) and (ii), using2-chloromethylpyrimidine and 3-phthalimidopropanethiol as the startingmaterials, the product isN-methyl-N'-[3-(2-pyrimidylmethylthio)propyl]thiourea.

EXAMPLE 61 4,6-bis-[2-N-Methylthioureido)ethylthiomethyl]pyrimidine

4,6-Pyrimidinedicarboxylic acid is converted to the diethyl ester whichis reduced with lithium aluminium hydride in tetrahydrofuran to give4,6-di(hydroxymethyl)-pyrimidine which on treatment with thionylchloride gives 4,6-di(chloromethyl)pyrimidine.

Using 4,6-di(chloromethyl)pyrimidine in the procedure of Example 59 givethe title compound.

EXAMPLE 62 N-Methyl-N'-[ 2(2-pyrimidylmethylthio)ethyl]urea

By the procedure of Example 24, 2-[(2-aminoethyl)thiomethyl]pyrimidineis reacted with methyl isocyanate to give the title compound.

EXAMPLE 63 N-Methyl-N'-[2-(2-(4-pyrimidyl)ethyl)thioethyl]thiourea

By the procedure of Example 17, using 4-(2-chloroethyl)pyrimidine,prepared by treating 4-(2-hydroxyethyl)pyrimidine with thionyl chloride,as the starting material, the title compound is prepared.

EXAMPLE 64

i. A mixture of 2-mercaptopyrimidine (5.6 g.) and3-bromopropylphthalimide (13.4 g.) in ethanol (100 ml.) containingsodium (1.15 g.) was heated under reflux for 20 hours affording2-(3-phthalimidopropylthio)pyrimidine, m.p. 81.5°-82.5° (fromethanol-water).

ii. Reaction of the phthalimido compound (3.7 g.) with hydrazine (1.86g.) followed by reaction of the product directly with methylisothiocyanate (0.83 g.), affordedN-methyl-N'-[3-(2-pyrimidylthio)propyl]thiourea (1.9 g.), m.p. 120°-121°(from ethanol-ether).

By the same procedure, using 4-me capto-2-trifluoromethylpyrimidine(prepared by reacting 4-hydroxy-2-trifluoromethylpyrimidine withphosphorus pentasulfide),N-methyl-N'-[3-((2-trifluoromethyl-4-pyrimidyl)thio)propyl[-thiourea isobtained.

EXAMPLE 65 N-Methy-N'-[2-(2-pyrimidylmethoxy)ethyl]thiourea

By the procedure of Example 38, 2-chloromethylpyrimidine prepared byreacting 2-hydroxymethylpyrimidine with thionyl chloride, is convertedto 2-(2 -chloroethoxymethyl)pyrimidine hydrochloride.

Using 2-(2-chloroethoxymethyl)pyrimidine in the procedure of Example 23gives the title compound.

EXAMPLE 66

By the procedure of Example 18, 2-[(2-aminoethyl)-thiomethyl]pyrimidineis reacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(2-pyrimidylmethylthio)ethyl]thiourea. Removing thebenzoyl group by the procedure of Example 18 giveN-[2-(2-pyrimidylmethlthio)ethyl]thiourea.

EXAMPLE 67N-(2-Dimethylaminoethyl)-N'-[2-(2-pyrimidylmethylthio)ethyl]-thiourea

Treatment of 2-[(2-aminoethyl)thiomethyl]pyrimidine with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 68

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-pyrimidylmethylthio)-                                       ethyl]thiourea             150 mg.                                            Sucrose                    70 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 69

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-pyrimidylmethylthio)-                                       ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 70 N-Methyl-N'-[2-(2-pyrazinylmethylthio)ethyl]thiourea

i. 2-Chloromethylpyrazine (6.4 g.) was added over 20 minutes to asolution freshly prepared from sodium (0.23 g.) in ethanol (50 ml.) towhich cysteamine hydrochloride (5.7 g.) had been added gradually at 0°and stirred at this temperature for 2 hours. The suspension finallyobtained was stirred at room temperature overnight, acidified withhydrochloric acid (pH 5) and concentrated under reduced pressure. Thedry residue was extracted with ethanol and the extracts filtered andconcentrated to give the crude product. Extraction with isopropylalcohol, with the removal of some polymeric material and the addition ofether gave a cream colored solid (3.5 g.), which was recrystallised fromethanol-ether to furnish 2-[(2-aminoethyl)thiomethyl]pyrazinehydrochloride, m.p. 144°-146 °.

ii. The amine hydrochloride (1.6 g.) was converted into the free baseusing potassium carbonate and reacted with methyl isothiocyanate (0.61g.) in ethanol in the usual way. Recrystallisation from ethanolfurnished N-methyl-N'-[2-(2-pyrazinylmethylthio)ethyl]thiourea (0.88g.), m.p. 99.5°-100.5 °. (Found: C, 44.6; H, 5.9; N, 22.8; S, 26.5; C₉H₁₄ N₄ S requires: C, 44.6; H, 5.8; N, 23.1; S, 26.5).

EXAMPLE 71

Using, in the procedure of Example 70, the following haloalkylpyrazines,which may be prepared by reacting the hydroxyalkylpyrazines with athionyl halide:

2-chloromethyl-5-methylpyrazine

2-chloromethyl-3-methylpyrazine

3-chloro-2-chloromethylpyrazine

3-amino-2-chloromethylpyrazine

2,3-di(chloromethyl)pyrazine

the products are, respectively:

N-methyl-N'-[2-((5-methyl-2-pyrazinyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((3-methyl-2-pyrazinyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((3-chloro-2-pyrazinyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((3-amino-2-pyrazinyl)methylthio)ethyl]-thiourea

2,3-bis- 2-(N-methylthioureido)ethylthiomethyl pyrazine.

Also, by the procedure of Example 70, reacting2-[(2-aminoethyl)thiomethyl]pyrazine with ethyl isothiocyanate givesN-ethyl-N-[2-(2-pyrazinylmethylthio)ethyl]thiourea.

In the procedure of Example 70, using 3-mercapto-propylamine in place ofcysteamline, the product isN-methyl-N'-[3-(2-pyrazinylmethylthio)propyl]thiourea.

EXAMPLE 72

3-Hydroxypyrazine-2-carboxylic acid is converted to the correspondingethyl ester and the ester is reduced with lithium aluminium hydride intetrahydrofuran to give 3-hydroxy-2-hydroxymethylpyrazine.

Treatment of 3-hydroxy-2-hydroxymethylpyrazine at room temperature withthionyl chloride gives 2-chloromethyl-3-hydroxypyrazine.

Using 2-chloromethyl-3-hydroxypyrazine in the procedure of Example 70,the product isN-methyl-N'-[2-((3-hydroxy-2-pyrazinyl)methylthio)ethyl]thiourea.

By the same procedure, using 3,6-dimethylpyrazine-2-carboxylic acid asthe starting material, the product isN-methyl-N'-[2-((3,6-dimethyl-2-pyrazinyl)methylthio)ethyl]-thiourea.

Reduction of 3-chloro-5-methyl-2-pyrazinecarboxylic acid (prepared byalkaline hydrolysis of the methyl ester) with diborane gives3-chloro-2-hydroxymethyl-5-methylpyrazine which, using the aboveprocedure, yieldsN-methyl-N'-[2-((3-chloro-5-methyl-2-pyrazinyl)methylthio)ethyl]thiourea.

EXAMPLE 73 N-Methyl-N'-[2-(2-(2-pyrazinyl)ethyl)thioethyl]thiourea

Using, in the procedure of Example 17, 2-(2-chloroethyl)pyrazine,prepared by reacting 2-(2-hydroxyethyl)-pyrazine with thionyl chloride,as the starting material gives the title compound.

EXAMPLE 74 N-Methyl-N'-[3-(2-pyrazinylthio)propyl]thiourea

Using, in the procedure of Example 64, 2-mercaptopyrazine as thestarting material, the title compound is obtained.

EXAMPLE 75 N-Methyl-N'-[2-(2-pyrazinylmethoxy)ethyl]thiourea

Using, in the procedure of Example 38, 2-chloromethylpyrazine as thestarting material, the product is the title compound.

EXAMPLE 76 N-Methyl-N'-[2-((2-pyrazinyl)methlthio)ethyl]urea

By the procedure of Example 24, 2-[(2-aminoethyl)-thiomethyl]pyrazine isreacted with methyl isocyanate to give the title compound.

EXAMPLE 77

By the procedure of Example 18, 2-[(2-aminoethyl)-thiomethyl]pyrazine isreacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(2-pyrazinylmethylthio)ethyl]thiourea. Removing thebenzoyl group by the procedure of Example 18 givesN-[2-(2-pyrazinylmethylthio)ethyl]thiourea.

EXAMPLE 78N-(2-Dimethylaminoethyl)-N'-[2-(2-pyrazinylmethylthio)ethyl]-thiourea

Treatment of 2-[(2-aminoethyl)thiomethyl]pyrazine with2-dimethylaminomethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 79

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-pyrazinylmethylthio)-                                       ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 80 N-Methyl-N'-[2-(3-pyridazinylmethylthio)ethyl]thiourea

By the procedure of Example 1, using 3-hydroxymethylpyridazine, theintermediate 3-[(2-aminoethyl)thiomethyl]pyridazine dipicrate, m.p.145°-148°, and the product,N-methyl-N'-[2-(3-pyridazinylmethylthio)ethyl]thiourea (recrystallisedfrom acetone-ether), m.p. 110°-111°, were obtained. (Found: C, 44.5; H,5.9, N, 23.0; S, 26.3. C₉ H₁₄ N₄ S₂ requires: C, 44.6; H, 5.8; N, 23.1;S, 26.5).

EXAMPLE 81

Using in the procedure of Example 1 the followinghydroxymethylpyridazines:

4-hydroxymethyl-6-methylpyridazine

4-hydroxymethyl-3,6-dimethylpyridazine

3-chloro-4-hydroxymethyl-6-methylpyridazine

4,5-di(hydroxymethyl)pyridazine

the products are, respectively:

N-methyl-N'-[2-((6-methyl-4-pyridazinyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-((3,6-dimethyl-4-pyridazinyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-((3-chloro-6-methyl-4-pyridazinyl)methylthio)ethyl]thiourea

4,5-bis-[2-(N-methylthioureido)ethylthiomethyl]pyridazine.

Using ethyl isothiocyanate in place of methyl isothiocyanate in theprocedure of Example 1, the corresponding N-ethyl compounds areprepared.

In the procedure of Example 1, using 4-hydroxymethyl-6-methylpyridazineand 3-mercaptopropylamine as the starting materials, the product isN-methyl-N'-[3-((6-methyl-4-pyridazinyl)methylthio)propyl]thiourea.

EXAMPLE 82

6-Amino-3-pyridazinecarboxylic acid is converted to the methyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofuranto give 6-amino-3-hydroxymethylpyridazine.

Using 6-amino-3-hydroxymethylpyridazine in the procedure of Example 1gives N-methyl-N'-[2-((6-amino-3-pyridazinyl)methylthio)ethyl]thiourea.

By the same procedure, using 6-hydroxy-3-pyridazinecarboxylic acid asthe starting material, the product isN-methyl-N'-[2-((6-hydroxy-3-pyridazinyl)methyl-thio)ethyl]thiourea.

Reduction of 6-chloro-3-pyridazinecarboxylic acid with diborane gives6-chloro-3-hydroxymethylpyridazine which, in the procedure of Example 1,yieldsN-methyl-N'-[2-((6-chloro-3-pyridazinyl)methylthio)ethyl]thiourea.

EXAMPLE 83 N-Methyl-N'-[2-(3-pyridazinylmethylthio)ethyl]urea

By the procedure of Example 24, 3-[(2-amino-ethyl)thiomethyl]pyridazineis reacted with methyl isocyanate to give the title compound.

EXAMPLE 84

By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]pyridazineis reacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(3-pyridazinylmethylthio)ethyl]thiourea. Removing thebenzoyl group by the procedure of Example 18 givesN-[2-(3-pyridazinylmethylthio)ethyl]thiourea.

EXAMPLE 85N-(2-Dimethylaminoethyl)-N'-[2-(3-pyridazinylmethylthio)-ethyl]thiourea

Treatment of 3-[(2-aminoethyl)thiomethyl]-pyridazine with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 86 N-Methyl-N'-[2-(3-pyridazinylmethoxy)ethyl]thiourea

By the procedure of Example 38, using 3-chloromethylpyridazine (preparedby treating 3-hydroxymethylpyridazine with thionyl chloride) as thestarting material, the product is the title compound.

EXAMPLE 87

3-Cyanomethylpyridazine is treated with aqueous sodium hydroxide to give3-pyridazineacetic acid.

3-Pyridazineacetic acid is esterified with anhydrous ethanolic hydrogenchloride and the resulting ethyl ester is reduced with lithium aluminumhydride in tetrahydrofuran to give 3-(2-hydroxyethyl)pyridazine.Treating this hydroxyethyl compound with thionyl chloride gives3-(2-chloroethyl)pyridazine.

Using 3-(2-chloroethyl)pyridazine as the starting material in theprocedure of Example 17 givesN-methyl-N'-[2-(2-(3-pyridazinyl)ethyl]thioethyl]thiourea.

EXAMPLE 88 N-Methyl-N'-[3-(3-pyridazinylthio)propyl]thiourea

Using 3-mercaptopyridazine as the starting material in the procedure ofExample 21, the title compound is obtained.

EXAMPLE 89

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-pyridazinylmethylthio)-                                     ethyl]thiourea             150 mg.                                            Lactose                    150 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a six membered unsaturated heterocyclic ringhaving two nitrogen atoms and four carbon atoms, said unsaturatedheterocyclic ring being pyrimidine, pyrazine or pyridazine, and Y is NHare exemplified by the following examples.

EXAMPLE 90

Using, in the procedure of Example 40 (a), the followinghaloalkylpyrimidines (which may be prepared by treating thehydroxyalkylpyrimidines with a thionyl halide):

2-chloromethylpyrimidine

5-bromomethylpyrimidine

2-chloromethyl-5-methylpyrimidine

5-bromo-2-bromomethylpyrimidine

2-bromomethyl-4-hydroxypyrimidine

4-amino-5-bromomethylpyrimidine

5-bromomethyl-2,4-dimethylpyrimidine

4-chloro-5-chloromethyl-2-methylpyrimidine

4,6-di(bromomethyl)pyrimidine

the products are, respectively:

N-methyl-N'-[2-(2-pyrimidylmethylamino)ethyl]thiourea

N-methyl-N'-[2-(5-pyrimidylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((5-methyl-2-pyrimidyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-bromo-2-pyrimidyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((4-hydroxy-2-pyrimidyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((4 -amino-5-pyrimidyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((2,4-dimethyl-5-pyrimidyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((4-chloro-2-methyl-5-pyrimidyl)methyl-amino)ethyl]thiourea

4,6-bis-[2-(N-methylthioureido)ethylaminomethyl]-pyrimidine.

Also, using in the procedure of Example 40 (a), 2-chloromethylpyrimidineand 1,3-diaminopropane, the product isN-methyl-N'-[3-(2-pyrimidylmethylamino)propyl]-thiourea.

EXAMPLE 91 N-Methyl-N'-[2-(2-pyrimidylmethylamino)ethyl]urea

By the procedure of Example 24, N-(2-pyrimidylmethyl)ethylenediamine isreacted with methyl isocyanate to give, after concentrating andseparating the residue by column chromatography, the title compound.

EXAMPLE 92 N-Methyl-N'-[2-(2-(4-pyrimidyl)ethyl)aminoethyl]thiourea

Usng, in the procedure of Example 40 (a), 4-(2-chloroethyl)pyrimidine(prepared by reacting 4-(2-hydroxyethyl)pyrimidine with thionylchloride) as the starting material, the title compound is prepared.

EXAMPLE 93

Reaction of 2-bromopyrimidine with 1,3-diaminopropane in ethanolcontaining sodium ethoxide gives 2-(3-aminopropylamino)pyrimidine whichon reaction with methyl isothiocyanate results in the production ofN-methyl-N'-[3-(2 -pyrimidylamino)propyl]thiourea.

Similarly, using 4-chloro-2-trifluoromethylpyrimidine (prepared bytreating 4-hydroxy-2-trifluoromethylpyrimidine with phosphorusoxychloride and dimethylaniline), the product isN-methyl-N'-[3-((2-trifluoromethyl-4-pyrimidyl)amino)propyl]thiourea.

EXAMPLE 94

By the procedure of Example 46, N-(2-pyrimidylmethyl)ethylenediamine isreacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(2-pyrimidylmethylamino)-ethyl]thiourea.

Removing the benzoyl group by the procedure or Example 46 givesN-[2-(2-pyrimidylmethylamino)ethyl]thiourea. Treatment with hydrobromicacid gives the hydrobromide salt.

EXAMPLE 95

Reacting 2-(3-aminopropylamino)pyrimidine, prepared by reacting2-bromopyrimidine with 1,3-diaminopropane, with benzoyl isothiocyanateby the procedure of Example 46 givesN-benzoyl-N'-[3-(2-pyrimidylamino)propyl]thiourea.

Removing the benzoyl group by the procedure of Example 46 givesN-[3-(2-pyrimidylamino)propyl]thiourea.

EXAMPLE 96N-(2-Dimethylaminoethyl)-N'-[2-(2-pyrimidylmethylamino)-ethyl]thiourea

Treating N-(2-pyrimidylmethyl)ethylenediamine with 2-dimethylaminoethylisothiocyanate, then concentrating and separating by columnchromatography by the procedure of Example 40 (a)(ii) gives the titlecompound.

EXAMPLE 97

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-pyrimidylmethylamino)-                                      ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 98

Using, in the procedure of Example 40 (a), the followinghaloalkylpyrazines:

2-chloromethylpyrazine

2-chloromethyl-5-methylpyrazine

2-chloromethyl-3-methylpyrazine

3-chloro-2-chloromethylpyrazine

3-amino-2-chloromethylpyrazine

2,3-di(chloromethyl)pyrazine

2-chloromethyl-3-hydroxypyrazine

2-chloromethyl-3,6-dimethylpyrazine

3-chloro-2-chloromethyl-5-methylpyrazine

2-(2-chloroethyl)pyrazine

the products are, respectively:

N-methyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((5-methyl-2-pyrazinyl)methylamino)ethyl]thiourea

N-methyl-N'-[2-((3-methyl-2-pyrazinyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3-chloro-2-pyrazinyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3-amino-2-pyrazinyl)methylamino)-ethyl]thiourea

2,3-bis-[2-(N-methylthioureido)ethylaminomethyl]pyrazine

N-methyl-N'-[2-((3-hydroxy-2-pyrazinyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3,6-dimethyl-2-pyrazinyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3-chloro-5-methyl-2-pyrazinyl)methyl-amino)ethyl]thiourea

N-methyl-N'-[2-(2-(2-pyrazinyl)ethyl)aminoethyl]-thiourea

Treatment of N-methyl-N'-[2-(2-(2-pyrazinyl)ethyl)-aminoethyl]thioureawith hydriodic acid gives the hydroiodate salt.

Also, in the procedure of Example 40, using 2-chloromethylpyrazine and1,3-diaminopropane, the product isN-methyl-N'-[3-(2-pyrazinylmethylamino)propyl]thiourea.

EXAMPLE 99 N-Methyl-N'-[2-(2-pyrazinylmethylamino)ethyl]urea

Reacting N-(2-pyrazinylmethyl)ethylenediamine with methyl isocyanate bythe procedure of Example 24, then concentrating and separating theresidue by column chromatography gives the title compound.

EXAMPLE 100 N-Methyl-N'-[3-(2-pyrazinylamino)propyl]thiourea

Reacting 2-chloropyrazine with 1,3-diaminopropane by the procedure ofExample 93 gives 2-(3-aminopropylamino)-pyrazine and reacting thisintermediate with methyl isothiocyanate gives the title compound.

EXAMPLE 101

Reacting 2-(3-aminopropylamino)pyrazine with benzoyl isothiocyanate bythe procedure of Example 46 givesN-benzoyl-N'-[3-(2-pyrazinylamino)propyl]thiourea. Removing the benzoylgroup by the procedure of Example 46 givesN-[3-(2-pyrazinylamino)propyl]thiourea.

Treating this compound with hydrochloric acid gives the hydrochloridesalt.

Reacting 2-(3-aminopropylamino)pyrazine with ethyl isothiocyanate by theprocedure of Example 53 givesN-ethyl-N'-[3-(2-pyrazinylamino)propyl]thiourea.

EXAMPLE 102N-(2-Dimethylaminoethyl)-N'-[2-(2-pyrazinylmethylamino)-ethyl]thiourea

By the procedure of Example 40 (a), treatingN-(2-pyrazinylmethyl)ethylenediamine with 2-dimethylaminoethylisothiocyanate gives the title compound.

EXAMPLE 103

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-pyrazinylmethylamino)-                                      ethyl]thiourea             200 mg.                                            Lactose                    150 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 104

Using, in the procedure of Example 40, the followingchloroalkylpyridazines (which may be prepared by treating thehydroxyalkylpyridazines with thionyl chloride):

3-chloromethylpyridazine

4-chloromethyl-6-methylpyridazine

4-chloromethyl-3,6-dimethylpyridazine

3-chloro-4-chloromethyl-6-methylpyridazine

4,6-di(chloromethyl)pyridazine

6-amino-3-chloromethylpyridazine

6-chloro-3-chloromethylpyridazine

3-chloromethyl-6-hydroxypyridazine

the products are, respectively:

N-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((6-methyl-4-pyridazinyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-((3,6-dimethyl-4-pyridazinyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3-chloro-6-methyl-4-pyridazinyl)methyl-amino)ethyl]thioure

4,6-bis-[2-(N-methylthioureido)ethylaminomethyl]pyridazine

N-methyl-N'-[2-((6-amino-3-pyridazinyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-((6-chloro-3-pyridazinyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-((6-hydroxy-3-pyridazinyl)methylamino)-ethyl]thiourea.

Treatment of N-methyl-N'-2-(3-pyridazinylmethylamino)ethyl]thiourea withhydrobromic acid gives the hydrobromide salt.

Also, by the procedure of Example 40, using 3-chloromethylpyridazine and1,3-diaminopropane, the product isN-methyl-N'-[3-(3-pyridazinylmethylamino)propyl]-thiourea.

EXAMPLE 105 N-Methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]urea

Reacting N-(3-pyridazinylmethyl)ethylenediamine with methyl isocyanateby the procedure of Example 24, then concentrating and separating theresidue by column chromatography gives the title compound.

EXAMPLE 106N-(2-Dimethylaminoethyl)-N'-[2-(3-pyridazinylmethylamino)-ethyl]thiourea

Reacting N-(3-pyridazinylmethyl)ethylenediamine with2-dimethylaminoiethyl isothiocyanate by the procedure of Example 40gives the title compound.

EXAMPLE 107 N-Methyl-N'-[3-(3-pyridazinylamino)propyl]thiourea

Using, in he procedure of Example 93, 3-chloropyridazine as the startingmaterial, the title compound is prepared.

EXAMPLE 108

Treating 3-(3-aminopropylamino)pyridazine, prepared by reacting3-chloropyridazine with 1,3-diaminopropane, with benzoyl isothiocyanateby the procedure of Example 46 givesN-benzoyl-N'-[3-(3-pyridazinylamino)propyl]-thiourea. Removing thebenzoyl group by the procedure of Example 46 givesN-[3-(3-pyridazinylamino)propyl]thiourea.

Reacting 3-(3-aminopropylamino)pyridazine with ethyl isothiocyanata bythe procedure of Example 53 givesN-ethyl-N-[3-(3-pyridazinylamino)propyl]thiourea.

EXAMPLE 109

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-pyridazinylmethylamino)-                                    ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a five membered unsaturated heterocyclic ringhaving one nitrogen atom, one sulphur or oxygen atom and three carbonatoms, said unsaturated heterocyclic ring being thiazole, isothiazole,onazole or isoxazole, and Y is oxygen or sulphur (sulphur is preferred)are exemplified by the following examples.

EXAMPLE 110

By the procedure of Example 1, using as the starting materials2-hydroxymethylthiazole and 4-hydroxymethylthiazole, were produced thefollowing intermediate amine salts:

2-[(2-aminoethyl)thiomethyl]thiazole dihydrobromide, m.p. 144°-147.5° C.

4-[(2-aminoethyl)thiomethyl]thiazole dihydrobromide, m.p. 197°-203° C.

These intermediate salts were reacted with methyl isothiocyanate by theprocedure of Example 1 to give:

N-methyl-N'-[2-(2-thiazolylmethylthio)ethyl]thiourea, recrystallisedfrom isopropyl acetate, m.p. 114°-116° C. (Found: C, 38.8; H, 5.4; N,17.0; S, 38.9. C₈ H₁₃ N₃ S₃ requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9)

N-methyl-N'-[2-(4-thiazolylmethylthio)ethyl]thiourea, recrystallisedfrom isopropyl acetate/isopropanol, m.p. 78°-80.5° C. (Found: C, 38.8;H, 5.3; N, 17.2; S, 38.7. C₈ H₁₃ N₃ S₃ requires: C, 38.8; H, 5.3; N,17.0; S, 38.9)

EXAMPLE 111

By the procedure of Example 21(i), using 2-mercaptothiazole as thestarting material, the intermediate amine salt,2-(3-aminopropylthio)thiazole dihydrobromide, m.p. 175°-178° C., wasprepared.

This intermediate amine salt was reacted with methyl isothiocyanate bythe procedure of Example 21(ii) to giveN-methyl-N'-[3-(2-thiazolylthio)propyl]thiourea, recrystallised fromwater, m.p. 67°-68° C. (Found: C, 38.6; H, 5.3; N, 16.9; S, 38.9. C₈ H₁₃N₃ S₃ requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).

EXAMPLE 112 N-Methyl-N'-[2-(5-thiazolylmethylthio)ethyl]thiourea

The reaction of 5-hydroxymethylthiazole (2.01 g.) with cysteaminehydrochloride (1.99 g.) in aqueous hydrobromic acid by the methoddescribed in Example 1(i)(a) gave 5-[(2-aminoethyl)thiomethyl]thiazoledihydrobromide (4.85 g.), m.p. 191°-194° (from methanol).

The reaction of 5-[(2-aminoethyl)thiomethyl]-thiazole (2.24 g.) withmethyl isothiocyanate (0.94 g.) in ethanol (10 ml.) gave a thioureawhich was purified by chromatography on a column of silica gel withethyl acetate as eluant. Recrystallisation from isopropyl acetate-methylethyl ketone-ether gaveN-methyl-N'-[2-(5-thiazolylmethylthio)ethyl]thiourea (2.1 g.), m.p.86°-88°. (Found: C, 38.6; H, 5.4; N, 16.9; S, 38.6. C₈ H₁₃ N₃ S₃requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).

EXAMPLE 113N-Methyl-N'-[2-((2-amino-4-thiazolyl)methylthio)ethyl]thiourea

A mixture of 2-amino-4-chloromethylthiazole hydrochloride (9.0 g.) andcysteamine hydrochloride (5.53 g.) in acetic acid (100 ml.) was heatedunder reflux for 18 hours. The crude product obtained afterconcentration was treated with picric acid in ethanol to afford2-amino-4-[(2-aminoethyl)thiomethyl]thiazole dipicrate, m.p.approximately 200°-210° (from ethanol).

The picrate was converted into the free base by addition of hydrochloricacid, removal of picric acid by toluene extraction, basification withpotassium carbonate and extraction of the aqueous residue withethanol-ether. Reaction of the base (1.89 g.) with methyl isothiocyanate(0.73 g.) in ethanol (10 ml.) in the usual way gave the crude thiourea.Chromatography on a column of silica gel with ethyl acetate as theeluant, followed by recrystallisation from isopropyl alcohol-isopropylacetate gaveN-methyl-N'-[2-((2-amino-4-thiazolyl)methylthio)ethyl]thiourea (1.0 g.),m.p. 136°-140°. (Found: C, 37.1; H, 5.5; N, 20.8; S, 36.3. C₈ H₁₄ N₄ S₃requires: C, 36.6; H, 5.4; H, 21.3; S, 36.7).

EXAMPLE 114

Using the following thiazoles as starting materials in the procedure ofExample 1:

2-hydroxymethyl-4-methylthiazole

4-chloromethyl-2-methylthiazole

2-chloro-4-chloromethylthiazole

2-bromomethyl-4,5-dimethylthiazole

4-ethyl-2-hydroxymethyl-5-methylthiazole

the products are, respectively:

N-methyl-N'-[2-((4-methyl-2-thiazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((2-methyl-4-thiazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((2-chloro-4-thiazolyl)methylthio)ethyl]-thiourea

N-methyl-N'-[2-((4,5-dimethyl-2-thiazolyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-((4-ethyl-5-methyl-2-thiazolyl)methylthio)-ethyl]thiourea.

By the same procedure, using ethyl isothiocyanate the correspondingN-ethyl thioureas are prepared.

EXAMPLE 115

2-Benzyl-4-thiazolecarboxylic acid is converted to the methyl ester andthe ester is reduced with lithium aluminium hydride in tetrahydrofurannto give 2-benzyl-4-hydroxymethylthiazole. Using this compound as thestarting material in the procedure of Example 1 givesN-methyl-N'-[2-((2-benzyl-4-thiazolyl)methylthio)ethyl]-thiourea.

By the same procedure, from the following compounds:

2,4-thiazoledicarboxylic acid

2-hydroxy-4-thiazolecarboxylic acid

the following products are obtained, respectively:

2,4-bis-[2-(N-methylthioureido)ethylthiomethyl]-triazole

N-methyl-N'-[2-((2-hydroxy-4-thiazolyl)methylthio)ethyl]thiourea

Reduction of 5-bromo-4-methyl-2-thiazolecarboxylic acid with diboraneyields 5-bromo-4-methyl-2-hydroxymethylthiazole which by the procedureof Example 1 may be converted toN-methyl-N'-[2-((5-bromo-4-methyl-2-thiazolyl)methylthio)-ethyl]thiourea.

EXAMPLE 116 N-Methyl-N'-[2-(4-thiazolylmethoxy)propyl]thiourea

By the same procedure of Example 28, using as the starting material4-chloromethylthiazole (prepared by reacting 4-hydroxymethylthiazolewith thionyl chloride) the title compound is prepared.

EXAMPLE 117 N-Methyl-N'-[2-(2-(4-thiazolyl)ethyl)thioethyl]thiourea

By the procedure of Example 17, using 4-(2-chloroethyl)thiazole, thetitle compound is prepared.

EXAMPLE 118 N-Methyl-N'-[2-(2-thiazolylmethylthio)ethyl]urea

By the procedure of Example 24, 2-[(2-aminoethyl)thiomethyl]thiazole isreacted with methyl isocyanate to give the title compound, m.p.65°-65.5° (from isopropyl acetate). (Found: C, 41.7; H, 5.6; N, 18.3; S,28.1. C₈ H₁₃ N₃ S₂ O requires: C, 41.5; H, 5.7; N, 18.2; S, 27.7).

EXAMPLE 119

By the procedure of Example 18, 2-[(2-aminoethyl)-thiomethyl]thiazole isreacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(2-thiazolymethylthio)ethyl]thiourea. Removing thebenzoyl group by the procedure of Example 18 givesN-[2-(2-thiazolylmethylthio)ethyl]thiourea. Treating this compound withhydrobromic acid gives the hydrobromide salt.

EXAMPLE 120N-(2-Dimethylaminoethyl)-N'-[2-(2-thiazolylmethylthio)ethyl]-thiourea

Treatment of 2-[(2-aminoethyl)thiomethyl]thiazole with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 121

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-thiazolylmethylthio)ethyl]-                                 thiourea                   200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 122 N-Methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea

A solution was prepared by the gradual addition of cysteaminehydrochloride (2.03 g.) to sodium (0.83 g.) dissolved in ethanol (50ml.) with stirring at 0° under a nitrogen atmosphere. After stirring for2 hours at 0°, 3-bromomethylisothiazole (3.2 g.) was added dropwise over15 minutes at 0°, the reaction mixture subsequently being set asideovernight at room temperature. Following acidification to pH 3.5 withhydrochloric acid, concentration and re-evaporation with ethanol, theresidue was dissolved in ethanol, filtered and concentrated to yield3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This wasconverted directly to the free base by treatment with aqueous potassiumcarbonate and extraction with ether. The extracts were dried overmagnesium sulphate, filtered and concentrated to yield the amine base asan oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methylisothiocyanate (0.66 g.) added, and the solution heated under reflux for30 minutes. Concentration, followed by purification of the crude productby chromatography on a column of silica gel with ethyl acetate as eluantfollowed by chromatography on a column of alumina with benzene/ethylacetate as eluant gaveN-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. (Found: C,38.9; H, 5.4 N, 16.5; S, 38.3. C₈ H₁₃ N₃ S₃ requires: C, 38.8; H, 5.3;N, 17.0; S, 38.9).

EXAMPLE 123N-Methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]-thiourea

The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) withcysteamine (from cysteamine hydrochloride (3.76 g.)) was performed underconditions similar to those described in Example 122. From the reactionthere was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazolehydrobromide, which, following recrystallisation from ethanol-ether andacetonitrile, gave needles (4.05 g.), m.p. 111°-112°. The amine base(2.73 g.) was isolated by basification with sodium hydroxide andextraction with chloroform and then dissolved in ethanol and treatedwith methyl isothiocyanate (0.78 g.). The solution was heated underreflux for 30 minutes, concentrated and the residue triturated withether to yield the crystalline thiourea (2.9 g.) m.p. 60°-61°.Recrystallisation from isopropyl acetate gaveN-methyl-N'-[2-((4-bromo-3-isothiazolyl)-methylthio)ethyl]thiourea (2.3g.) as needles, m.p. 62°-63°. (Found: C, 29.5; H, 3.8; N, 12.9; Br,24.6; S, 29.3. C₈ H₁₂ BrN₃ S₃ requires: C, 29.5; H, 3.7; N, 12.9; Br,24.5; S, 29.5).

EXAMPLE 124

Using the following halomethylisothiazoles as starting materials in theprocedure of Example 122:

3-bromomethyl-4-chloroisothiazole

4-bromo-5-chloromethyl-3-methylisothiazole

the products are, respectively:

N-methyl-N'-[2-((4-chloro-3-isothiazolyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-((4-bromo-3-methyl-5-isothiazolyl)methylthio)ethyl]thiourea.

By the same procedure, using ethyl isothiocyanate the correspondingN-ethyl thiourea compounds are obtained.

EXAMPLE 125

Reacting 4-hydroxymethyl-3-methylisothiazole (3.0 g.) with cysteaminehydrochloride (2.8 g.) in 48% aqueous hydrobromic acid (50 ml.) by theprocedure of Example 1 gives3-methyl-4-[(2-aminoethyl)thiomethyl]-isothiazole hydrobromide. The baseis obtained by basifying with aqueous potassium carbonate, extractingwith chloroform, drying the extracts over magnesium sulphate andconcentrating. Reacting the amine (5.0 g.) with methyl isothiocyanate(1.94 g.) in ethanol (25 ml.) under reflux for 30 minutes and purifyingthe product on a column of alumina with benzene as eluant givesN-methyl-N'-[2-(3-methyl-4-isothiazolylmethylthio)ethyl]thiourea.(Found: C, 40.8; H, 5.9; N, 16.1; S, 36.4. C₉ H₁₅ N₃ S₃ requires: C,41.3; H, 5.8; N, 16.1; S, 36.8).

3,5-Dimethyl-4-isothiazolecarboxylic acid is converted to the ethylester and the ester is reduced with lithium aluminium hydride intetrahydrofuran to give 4-hydroxymethyl-3,5-dimethylisothiazole. Usingthis hydroxymethyl compound as the starting material for the aboveprocess givesN-methyl-N'-[2-((3,5-dimethyl-4-isothiazolyl)methylthio)ethyl]thiourea.

Similarly, using 3,5-isothiazoledicarboxylic acid the product is3,5-bis-[2-(N-methylthioureido)ethylthiomethyl]isothiazole.

EXAMPLE 126N-Methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]urea

Reacting 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole with methylisocyanate by the procedure of Example 24 gives the title compound.

EXAMPLE 127 N-Methyl-N'-[3-(3-isothiazolylmethoxy)propyl]thiourea

Using 3-bromomethylisothiazole in the procedure of Example 28 gives thetitle compound.

EXAMPLE 128 N-Methyl-N'-[2-(2-(3-isothiazolyl)ethyl)thioethyl]thiourea

3-Isothiazoleacetic acid is converted to the methyl ester and the esteris reduced with lithium aluminium hydride in tetrahydrofuran to give3-(2-hydroxyethyl)isothiazole. Reacting this hydroxyethyl compound withthionyl chloride gives 3-(12-chloroethyl)isothiazole. Using3-(2-chloroethyl)isothiazole in the procedure of Example 17 gives thetitle compound.

EXAMPLE 129

By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]isothiazoleis reacted with benzoyl isothiocyanate to giveN-benzoyl-N'-[2-(3-isothiazolylmethylthio)ethyl]-thiourea. Removing thebenzoyl group by the procedure of Example 18 givesN-[2-(3-isothiazolylmethylthio)ethyl]thiourea.

EXAMPLE 130N-(2-Dimethylaminoethyl)-N'-[2-(3-isothiazolylmethylthio)-ethyl]thiourea

Treatment of 3-[(2-aminoethyl)thiomethyl]isothiazole with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 131

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-isothiazolylmethylthio)-                                    ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 132 N-Methyl-N'-[3-(2-oxazolylthio)propyl]thiourea

i. Hydrochloric acid (90 ml.) was added to potassium thiocyanate inethanol (1.8 l.) with stirring. Following filtration from inorganicmaterial, glycollaldehyde (35.9 g.) was added and the resulting solutionwas heated under reflux for 24 hours. Concentration, followed by coolingafforded a white solid, which following recrystallisation from ethanolafforded oxazole-2-thiol (30 g.) m.p. 143°-144°.

ii. 3-Bromopropylphthalimide (13.4 g.) was added to a stirred solutionof sodium ethoxide (from 1.15 g. sodium) and oxazole-2-thiol (5.1 g.) inethanol (100 ml.). The resultant solution was heated under reflux for2.5 hours and concentrated under reduced pressure. The residue wastriturated with water (100 ml.) to afford2-(3-phthalimidopropylthio)oxazole (14 g.), m.p. 101°. Recrystallisationfrom ethanol gave the pure oxazole, m.p. 102°-103°.

iii. Hydrazine hydride (5.3 g.) was added carefully to a solution of2-(3-phthalimidopropylthio)oxazole (10. g.) in ethanol (173 ml.) withstirring. The solution was then heated under reflux for 25 minutes.After cooling, and filtration from phthalhydrazide, the filtrate wasconcentrated under reduced pressure and the residue was re-evaporatedwith ethanol to yield crude 2-(3-aminopropylthio)oxazole which waswashed twice with ether and dissolved in ethanol (60 ml.). Methylisothiocyanate (2.54 g.) was added and the solution was heated underreflux for 30 minutes. Following cooling and filtration from insolublematerial, the filtrate was concentrated to an oil which waschromatographed on a column of silica gel with ethyl acetate as eluant.The product obtained crystallised from ethanol-ether-n-hexane to giveN-methyl-N'-[3-(2-oxazolylthio)propyl]thiourea (2.4 g.), m.p. 43°-45°.(Found: C, 41.7; H, 5.9; N, 18.3; S, 27.5. C₈ H₁₃ N₃ OS₂ requires: C,41.5; H, 5.7; N 18.2; S, 27.7).

EXAMPLE 133 N-Methyl-N'-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea

i. The reaction of 4-methyloxazole-2-thiol (5.8 g.) with3-bromopropylphthalimide (13.4 g.) using the conditions described inExample 132 afforded 4-methyl-2-(3-phthalimidopropylthio)oxazole (14g.), m.p. 92°-93° (ethanol-ether).

ii. Treatment of the phthalimide compound (3.0 g.) with hydrazine (1.53g.) followed by reaction of the product directly with methylisothiocyanate (0.73 g.) using the conditions described in Example 132afforded N-methyl-N'-[3-(4-methyl-2-oxazolyl)thiopropyl]thiourea (1.0g.). m.p. 73°-74° (from ethanol-n-hexane). (Found: C, 44.0; H, 6.2; N,17.1; S, 25.9. C₉ H₁₅ N₃ OS₂ requires: C, 44.1; H, 6.2; N, 17.1; S,26.1).

EXAMPLE 134

Using the following 2-(chloroethyl)oxazoles as starting materials in theprocedure of Example 17:

5-(2-chloroethyl)-4-methyloxazole

5-(2-chloroethyl)-4-trifluoromethyloxazole

the products are, respectively:

N-methyl-N'-[2-(2-(4-methyl-5-oxazolyl)ethyl)thioethyl]thiourea

N-methyl-N'-[2-(2-(4-trifluoromethyl-5-oxazolyl)ethyl)-thioethyl]thiourea.

Also, using 2-amino-5-(2-chloroethyl)oxazole (prepared by reacting2-amino-5-(2-hydroxyethyl)oxazole with thionyl chloride) in theprocedure of Example 17 givesN-methyl-N'-[2-(2-(2-amino-5-oxazolyl)ethyl)thioethyl]thiourea.

Example 135

Methyl 5-benzyl-4-oxazolecarboxylate is reduced with lithium aluminiumhydride in tetrahydrofuran to give 5-benzyl-4-hydroxymethyloxazole,which on reaction with thionyl chloride is converted to5-benzyl-4-chloromethyloxazole.

Using 5-benzyl-4-chloromethyloxazole as the staring material,N-methyl-N'-[2-((5-benzyl-4-oxazolyl)-methylthio)ethyl]thiourea isprepared by the procedure of Example 1(i)(b) and (ii).

By the same procedure, using 2,5-dimethyl-4-oxazolecarboxylic acid, theproduct isN-methyl-N'-[2-((2,5-dimethyl-4-oxazolyl)methylthio)ethyl]thiourea.

Also, by the same procedure, using 4,5-oxazolediacarboxylic acid,4,5-bis-[2-(N-methylthioureido)ethylthiomethyl]oxazole is prepared.

Reduction of 5-chloro-2-methyl-4-oxazolecarboxylic acid with diborane tothe corresponding 4-hydroxymethyl compound, conversion of this to the4-chloromethyl compound and using this chloromethyl compound as thestarting material gives, by the procedure of Example 1(i)(b) and (ii),N-methyl-N'-[2-((5-chloro-2-methyl-4-oxazolyl)methylthio)ethyl]thiourea.

By the same procedure, using 5-chloro-4-chloromethyl-2-methyloxazole(prepared from the corresponding 4-carboxylic acid by the diboranereduction procedure described above) and 3-phthalimidopropanethiol, theproduct isN-methyl-N'-[3-((5-chloro-2-methyl-4-oxazolyl)methylthio)-propyl]thiourea.

Example 136 N-Methyl-N'-[2-((4-methyl-5-oxazolyl methylthio)ethyl]urea

By the procedure of Example 1(i)(b), using4-methyl-5-chloromethyloxazole as the starting material,5-](2-aminoethyl)thiomethyl]-4-methyloxazole is prepared.

Reacting 5-[(2-aminoethyl)thiomethyl]-4-methyl-oxazole with methylisocyanate by the procedure of Example 24 gives the title compound.

EXAMPLE 137 N-Methyl-N'-[2-((5-methyl-4-oxazolyl)methoxy)ethyl]thiourea

By the procedure of Example 38, 5-chloromethyl-4-methyloxazole isconverted to 4-(2-chloroethoxymethyl)-5-methyloxazole.

Using 4-(2-chloroethoxymethyl)-5-methyloxazole hydrochloride (preparedby treating the base with hydrochloric acid) in the procedure of Example23 gives the title compound.

EXAMPLE 138

5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with benzoylisothiocyanate by the procedure of Example 18 to giveN-benzoyl-N'-[2-((4-methyl-5-oxazolyl)-methylthio)ethyl]thiourea.Removing the benzoyl group by the procedure of Example 18 givesN-[2-((4-methyl-5-oxazolyl)methylthio)ethyl]thiourea.

Also, reacting 5-[(2-aminoethyl)thiomethyl]-4-methyloxazole with ethylisothiocyanate by the procedure of Example 1 givesN-ethyl-N'-[2-((4-methyl-5-oxazolyl)-methylthio)ethyl]thiourea.

EXAMPLE 139N-(2-Dimethylaminoethyl)-N'-[2-((4-methyl-5-oxazolyl)methyl-thio)ethyl]thiourea

5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 togive the title compound.

EXAMPLE 140

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[3-(2-oxazolylthio)propyl]-                                       thiourea                   150 mg.                                            Sucrose                    75 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 141

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[3-(4-methyl-2-oxazolyl)-                                         thiopropyl]thiourea        200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 142 N-Methyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea

a. A solution of 3-chloromethylisoxazole (5.8 g.) and cysteaminehydrochloride (6.25 g.) in aqueous hydrobromic acid (48%, 100 ml.) washeated under reflux for 6 hours. Concentration in the presence of waterand subsequently n-propanol, followed by recrystallisation of theresidue from isopropyl alcohol-ethanol afforded3-[(2-aminoethyl)-thiomethyl]isoxazole hydrobromide, m.p. 131°-133°.(Found: Br, 33.6; S, 13.7. C₆ H₁₀ N₂ OS.HBr requires: Br, 33.4; S,13.4).

b. A solution of 3-[(2-aminoethyl)thiomethyl]isoxazole (2.44 g.)extracted from the hydrobromide and potassium carbonate withether-ethanol (3:1) and methyl isothiocyanate (1.36 g.) in absoluteethanol (40 ml.) was heated under reflux for 1.5 hours. Concentrationfollowed by chromatographic purification on a column of silica gel wasether as eluant affordedN-methyl-N'-[2-(3-isoxazolyl-methylthio)ethyl]thiourea as a colorlessoil (2.5 g.). (Found: C, 41.3; H, 6.2; N, 18.2; S, 27.3. C₈ H₁₃ N₂ O₂ Srequires C, 41.5; H, 5.7; N, 18.2; S, 27.7).

EXAMPLE 143

Using the following chloromethylisoxazoles (prepared from thecorresponding hydroxymethylisoxazoles by treatment thereof with thionylchloride) as starting materials in the procedure of Example 142:

3-chloromethyl-5-methylisoxazole

3-bromo-5-chloromethylisoxazole

4-chloromethyl-3,5-dimethylisoxazole

4-(2-chloroethyl)-5-methylisoxazole

the products are, respectively:

N-methyl-N'-[2-(5-methyl-3-isoxazolylmethylthio)ethyl]-thiourea

N-methyl-N'-[2-(3-bromo-5-isoxazolylmethylthio)ethyl]-thiourea

N-methyl-N'-[2-(3,5-dimethyl-4-isoxazolylmethylthio)ethyl]-thiourea

N-methyl-N'-[2-(2-(5-methyl-4-isoxazolyl)ethylthio)ethyl]-thiourea.

EXAMPLE 144

Using, in the procedure of Example 142, 3-mercaptopropylamine in placeof cysteamine, the product is N-methylN'-[3-(3-isoxazolylmethylthio)propyl]thiourea.

EXAMPLE 145

Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole methyl isocyanate bythe procedure of Example 24 givesN-methyl-N'[2-(3-isoxazolylmethylthio)ethyl]urea.

EXAMPLE 146

By the procedure of Example 38, 3-chloromethylisoxazole is converted to3-(2-chloroethoxymethyl)isoxazole which is then reacted with methylisothiocyanate to giveN-methyl-N'-[2-(3-isoxazolylmethoxy)ethyl]thiourea.

EXAMPLE 147

3-(2-Aminoethyl)thiomethyl]isoxazole is reacted with benzoylisothiocyanate by the procedure of Example 18 to giveN-benzoyl-N'-[2-(3-isoxazolylmethylthio)ethyl-thiourea. Removing thebenzoyl group by the procedure of Example 18 givesN-[2-(3-isoxazolylmethylthio)ethyl]thiourea.

EXAMPLE 148

Reaction of 3-[(2-aminoethyl)thiomethyl]isoxazole by the procedure ofExample 142(b) with the following isothiocyanates:

ethyl isothiocyanate

propyl isothiocyanate

2-dimethylaminoethyl isothiocyanate

gives the follwing products, respectively:

N-ethyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea

N-propyl-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea

N-(2-dimethylaminoethyl)-N'-[2-(3-isoxazolylmethylthio)ethyl]thiourea.

EXAMPLE 149

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-isoxazolyl-                                                 methylthio)ethyl]thiourea  200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a five membered unsaturated heterocyclic ringhaving one nitrogen atom, one sulphur or oxygen atom and three carbonatoms, said unsaturated heterocyclic ring being thiazole, isothiazole,oxazole or isoxazole, and Y is NH are exemplified by the followingexamples.

EXAMPLE 150

Using in the procedure of Example 40, the following halomethylthiazoles(which may be prepared by treating the hydroxymethylthiazoles with athionyl halide):

2-chloromethylthiazole

4-chloromethylthiazole

5-chloromethylthiazole

2-amino-4-chloromethylthiazole

2-chloromethyl-4-methylthiazole

2-chloro-4-chloromethylthiazole

2-bromomethyl-4,5-dimethylthiazole

2-benzyl-4-chloromethylthiazole

2,4-di(chloromethyl)thiazole

5-bromo-2-chloromethyl-4-methylthiazole

4-chloromethyl-2-hydroxythiazole

the products are, respectively:

N-methyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-(4-thiazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-(5-thiazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((2-amino-4-thiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'[2-((4-methyl-2-thiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((2-chloro-4-thiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'[2-((4,5-dimethyl-2-thiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((2-benzyl-4-thiazolyl)methylamino)ethyl]-thiourea

2,4-bis-[2-(N-methylthioureido)ethylaminomethyl]thiazole

N-methyl-N'-[2-((5-bromo-4-methyl-2-thiazolyl)methyl-amino)ethyl]thiazole

N-methyl-N'-[2-((2-hydroxy-4-thiazolyl)methylamino)-ethyl]thiourea.

Similarly, using ethyl isothiocyanate, the corresponding N-ethylcompounds are obtained.

Treatment of N-methyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea withhydrochloric acid gives the hydrochloride salt. Similarly, treatmentwith maleic acid in ethanol gives the maleate salt.

Als , using in the procedure of Example 40, 2-chloromethylthiazole and1,3-diaminopropane as the starting materials, the product isN-methyl-N'-[3-(2-thiazolylmethylamino)propyl]thiourea.

EXAMPLE 151 N-Methyl-N'-[2-(2-(4-thiazolyl)ethyl)aminoethyl]thiourea

Using 4-(2-chloroethyl)thiazole in the procedure of Example 40 gives thetitle compound

EXAMPLE 152 N-Methyl-N'-[3-(2-thiazolylamino)propyl]thiourea

Using 2-aminothiazole as the starting material in the procedure ofExample 53 gives the title compound.

EXAMPLE 153 N-Methyl-N'-[2-(2-thiazolylmethylamino)ethyl]urea

N-(2-Thiazolylmethyl)ethylenediamine, prepared by reactingethylenediamine with 2-chloromethylthiazole by the procedure of Example40, is reacted with methyl isocyanate by the procedure of Example 24 togive, after concentrating and separating by column chromatography, thetitle compound.

EXAMPLE 154

By the procedure of Example 46, reacting 2-(3-aminopropylamino)thiazoleprepared from 2-aminothiazole by the method of Example 53)with benzoylisothiocyanate gives N-benzoyl-N'-[3-(2-thiazolylamino)propyl]thiourea.Removing the benzoyl group by the procedure of Example 46 givesN-[3-(2-thiazolylamino)propyl]thiourea.

By the same procedure, using 3-aminoisothiazole,N-benzoyl-N'-[3-(3-isothiazolylamino)propyl]thiourea is prepared and thebenzoyl group is removed to giveN-[3-(3-isothiazolylamino)propyl]thiourea.

EXAMPLE 155N-(2-Diamethylaminoethyl)-N'-[2-(2-thiazolylmethylamino)ethyl]-thiourea

Treating N-(2-thiazolylmethyl)ethylenediamine with 2-dimethylaminoethylisothiocyanate by the procedure of Example 40, then concentrating andseparating by column chromatography gives the title compound.

EXAMPLE 156

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-thiazolylmethylamino)-                                      ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 157

Using in the procedure of Example 40(a), the followinghaloalkylisothiazoles:

3-bromomethylisothiazole

4-bromo-3-bromomethylisothiazole

5-chloro-3-bromomethylisothiazole

4-bromo-5-chloromethyl-3-methylisothiazole

4-chloromethyl-3-methylisothiazole

4-bromomethyl-3,5-dimethylisothiazole

3,5-di(bromomethyl)isothiazole

3-(2-chloroethyl)isothiazole

the products are, respectively:

N-methyl-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((5-chloro-3-isothiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((4-bromo-3-methyl-5-isothiazolyl)-methylamino)ethyl]thioure

N-methyl-N'-[2-((3-methyl-4-isothiazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-((3.5-dimethyl-4-isothiazolyl)methylamino)ethyl]thiourea

3,5-bis-[2-(N-methylthioureido)ethylaminomethyl]isothiazole

N-methyl-N'-[2-(2-(3-isothiazolyl)ethyl)aminoethyl]-thiourea.

Also, by the preocedure of Example 40(a), using ethyl isothiocyanate,the corresponding N-ethyl compounds are prepared.

IN addition, using in the procedure of Example 40(a),3-bromomethylisothiazole and 1,3-diaminopropane as the startingmaterials, the product isN-methyl-N'-[3-(3-isothiaziolylmethylamino)propyl]thiourea.

EXAMPLE 158 N-Methyl-N'-[2-(3-isothiazolylmethylamino)ethyl]urea

N-(3-Isothiazolylmethyl)ethylenediamine, prepared by reactingethylenediamine with 3-bromomethylisothiazole by the procedure ofExample 40(a), is reacted with methyl isocyanate by the procedure ofExample 24 to give, after concenrating and separating by columnchromatography, the title compound.

EXAMPLE 159

By the procedure of Example 40(a) (ii),N-(3-isothiazolylmethyl)ethylenediamine is reacted with2-dimethylaminoethyl isothiocyanate to giveN-(2-dimethylaminoethyl)-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea.Reacting with hydrobromic acid gives the hydrobromide salt.

EXAMPLE 160

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-isothiazolylmethyl-                                         amino)ethyl]thiourea       200 mg.                                            Sucrose                    70 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 161

Using, in the procedure of Example 40(a), the followinghaloalkyloxazoles:

5-(2-chloroethyl)-4-methyloxazole

5-(2-chloroethyl)-4-trifluoromethyloxazole

2-amino-5-(2-chloroethyl)oxazole

the products are, respectively:

N-methyl-N'-[2-(2-(4-methyl-5-oxazolyl)ethyl)aminoethyl]thiourea

N-methyl-N'-[2-(2-(4-trifluoromethyl-5-oxazolyl)ethyl)-aminoethyl]thiourea

N-methyl-N'-[2-(2-(2-amino-5-oxazolyl)ethyl)aminoethyl]-thiourea.

By the same procedure, using ethyl isothiocyanate, the correspondingN-ethyl compounds are prepared.

EXAMPLE 162

Using 5-benzyl-4-chloromethyloxazole (prepared by converting5benzyl-4-oxazolecarboxylic acid to the methyl ester, then reducing theester with lithium aluminium hydride in tetrahydrofuran and treating theresulting 5-benzyl-4-hydroxymethyloxazole with thionyl chloride) in theprocedure of Example 40(a), the product isN-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]thiourea.

By the same procedure, using the following as starting materials:

2,5-dimethyl-4-oxazolecarboxylic acid

4,5-oxazoledicarboxylic acid

the following products are obtained, respectively:

N-methyl-N'-[2-((2,5-dimethyl-4-oxazolyl)methylamino)-ethyl]thiourea

4,5-bis-[2-(N-methylthioureido)ethylaminomethyl]oxazole.

EXAMPLE .sub.≲

Reduction of 5-chloro-2-methyl-4-oxazolecarboxylic acid with diboraneand conversion of the resulting 4-hydroxymethyl compound with thionylchloride to the corresponding chloromethyl analog which is then used asthe starting material in the process of Example 40(a) givesN-methyl-N'-[2-((5-chloro-2-methyl-4-oxazolyl)methylamino)ethyl]thiourea.

Using in the procedure of Example 40(a),5-chloro-4-chloromethyl-2-methyloxazole (prepared from the corresponding4-carboxylic acid compound by the diborane reduction/thionyl chlorideprocedure described above) and 1,3-diaminopropane as the startingmaterials, the product isN-methyl-N'-[3-((5-chloro-2-methyl-4-oxazolyl)methylamino)propyl]thiourea.

EXAMPLE 164N-(2-Dimethylaminoethyl)-N'-[2-(2-(4-methyl-5-oxazolyl)-ethyl)aminoethyl]thiourea

By the procedure of Example 40(a)(ii),N-[2-(4-methyl-5-oxazolyl)ethyl]ethylenediamine [prepared by reactingethylenediamine with 5-(2-chloroethyl)-4-methyloxazole] is reacted with2-dimethylaminoethyl isothiocyanate to give the titel compound.

EXAMPLE 165

    ______________________________________                                        Ingredients                 Amounts                                           ______________________________________                                        N-Methyl-N'-[2-(2-(4-methyl-5-oxazolyl)ethyl)-                                aminoethyl]thiourea         200 mg.                                           Lactose                     100 mg.                                           ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 166

Using, in the procedure of Example 40, the followingchloroalkylisoxazoles:

3-chloromethylisoxazole

3-chloromethyl-5-methyloxazole

3-bromo-5-chloromethylisoxazole

4-chloromethyl-3,5-dimethylisoxazole

4-(2-chloroethyl)-5-methylisoxazole

the products are, respectively:

N-methyl-N'-[2-(3-isoxazolylmethylamino)ethyl]thiourea

N-methyl-N'-[2-(5-methyl-3-isoxazolylmethylamine)-ethyl]thiourea

N-methyl-N'-[2-(3-bromo-5-isoxazolylmethylamino)-ethyl]thiourea

N-methyl-N'-[2-(3,5-dimethyl-4-isoxazolylmethylamino)-ethyl]thiourea

N-methyl-N'-[2-(2-(5-methyl-4-isoxazolyl)ethylamino)-ethyl]thiourea.

EXAMPLE 167

Using in the procedure of Example 40, 3-chloromethylisoxazole and1,3-diaminopropane as the starting materials, the product isN-methyl-N'-[3-(3-isoxazolylmethylamino)propyl]thiourea.

EXAMPLE 168

N-(3-Isoxazolylmethyl)ethylenediamine is reacted with methyl isocyanateby the procedure of Example 24 to give, after concentrating andseparating by column chromatography,N-methyl-N'-[2-(3-isoxazolylmethylamino)-ethyl]urea.

EXAMPLE 169

By the procedure of Example 40(a)(ii),N-(3-isoxazolylmethyl)ethylenediamine is reacted with the followingisothiocyanates:

ethyl isothiocyanate

propyl isothiocyanate

2-dimethylaminoethyl isothiocyanate

to give, respectively:

N-ethyl-N'-[2-(3-isoxazolylmethylamino)ethyl]thiourea N-propyl-N'-[2-(3-isoxazolylmethylamino)ethyl]thiourea

N-2-dimethylaminoethyl)-N'-[2-(3-isoxazolylmethyl-amino)ethyl]thiourea.

EXAMPLE 170

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-isoxazolylmethylamino)-                                     ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a triazole ring and Y is oxygen or sulphur(sulphur is preferred) are exemplified by the following examples.

EXAMPLE 171 N-Methyl-N'-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]thiourea

By the procedure of Example 1,3-[(2-aminoethyl)-thiomethyl]-1,2,4-triazole dihydrobromide, m.p.177°-179°, was prepared.

Reacting this intermediate salt with methyl isothiocyanate by theprocedure of Example 1 givesN-methyl-N'-[2-(3-(1,2,4-triazolyl)methylthio)ethyl]thiourea,recrystallised from ethanol/ether, m.p. 97°-99° C. (Found: C, 36.1; H,5.7; N, 30.1; S, 28.0. C₇ H₁₃ N₅ S₂ requires: C, 36.3; H, 5.7; N, 30.3;S, 27.7).

EXAMPLE 172N-Methyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)-ethyl]thiourea

Ethoxyacetyl chloride (57 g.) was added slowly to a stirred solution of4-methylthiosemicarbazide (53.5 g.) in dry pyridine (500 ml.) at 0°-5°.The mixture was allowed to attain room temperature and stirring wascontinued for 18 hours. Following concentration under reduced pressurethe residue was treated with a solution of sodium (21.4 g.) in ethanol(500 ml.) and the mixture was heated under reflux for 24 hours.Following concentration and acidification with hydrochloric acid a solidwas obtained. After partial concentration the solid was collected andrecrystallised from ethyl acetate to give3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g.), m.p.137°-138°.

The thione (44 g.) was desulphurised by slow addition to a solutionprepared from nitric acid (75 ml.), water (150 ml.) and sodium nitrite(1.5 g.) at 15°-20°. Following subsequent basification with sodiumcarbonate and concentration, the residue was extracted withethanol-ether 1:1 and distilled to afford 3-ethoxymethyl-4-methyl1,2,4-triazole (30 g.), b.p. 154°-156°/0.05 mm. The above compound (15g.) dissolved in 48% aqueous hydrobromic acid (150 ml.) was heated underreflux for 24 hours, concentrated to dryness and the residue obtained (amixture of 4-methyl-3-bromomethyl-1,2,4-triazole and4-methyl-3-hydroxymethyl-1,2,4-triazole) was used directly in thereaction with cysteamine hydrochloride and hydrobromic acid as describedin Example 1 (i)(a) to give 3-(2-aminoethyl)-4-methyl-1,2,4-triazoledihydrobromide, m.p. 175°-177°.

Reaction of 3-(2-aminoethyl)-4-methyl-1,2,4-triazole dihydrobromide withmethyl isothiocyanate by the procedure of Example 1(ii) givesN-methyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)enthyl]thiourea,which is recrystallised from water, m.p. 154°-155°. (Found: C, 39.3; H,6.0; N, 28.7; S, 26.2. C₈ H₁₅ N₅ S₂ requires: C, 39.2; H, 6.2; N, 28.5;S, 26.1).

EXAMPLE 1733,5-bis-[2-(N-Methylthioureido)ethylthiomethyl)]-1,2,4-triazole

i. The reaction of 3,5-di(hydroxymethyl)-1,2,4-triazole (90 g.; obtainedfrom 1,2,4-triazole and excess formaldehyde at elevated temperatures)with cysteamine hydrochloride (17.3 g.) by the procedure described inExample 1 (i)(a) afforded3,5-bis-[(2-aminoethyl)thiomethyl]-1,2,4-triazole trihydrobromide (4.7g.), m.p. 214°-215°.

ii. The reaction of 3,5-bis-[(2-aminoethyl)thiomethyl]-1,2,4-triazole(from 6.5 g. trihydrobromide) with methyl isothiocyanate (1.93 g.)afforded the bis-thiourea which was purified by passage through a columnof silica gel with ethanol as eluant. Trituration with isopropylacetate, followed by recrystallisation from ethanol-ether afforded3,5-bis-[2-(N-methylthioureido)ethylthiomethyl]-1,2,4-triazole (0.9 g.),m.p. 133°-135° . (Found: C, 35.7; H, 5.9; N, 24.6. C₁₂ H₂₃ N₇ S₄ 0.5 H₂O requires: C, 35.8; H, 6.1; N, 24.3).

EXAMPLE 174

By the procedure of Example 1 using the following hydroxymethyltriazoles as starting materials:

2-benzyl-3-hydroxymethyl-1,2,4-triazole

3-amino-5-hydroxymethyl-1,2,4-triazole

3-bromo-5-hydroxymethyl-1,2,4-triazole

1-benzyl-4-hydroxymethyl-1,2,3-triazole

the products are, respectively:

N-methyl-N'-[2-(2-benzyl-3-(1,2,4-triazolyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-(3-amino-5-(1,2,4-triazolyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-(3-bromo-5-(1,2,4-triazolyl)methylthio)-ethyl]thiourea

N-methyl-N'-[2-(1-benzyl-4-(1,2,3-triazolyl)methylthio)-ethyl]thiourea.

Using 3-amino-5-hydroxymethyl-1,2,4-triazole and 3-mercaptopropylamineas starting materials in the procedure of Example 1 givesN-methyl-N'-[3-(3-amino-5-(1,2,4-triazolyl)-methylthio)propyl]thiourea.

EXAMPLE 175

Converting 5-methyl-4-(1,2,3-triazole)carboxylic acid to the methylester and reducing the ester with lithium aluminium hydride intetrahydrofuran gives 4-hydroxymethyl-5-methyl-1,2,3-triazole.

Using 4-hydroxymethyl-5-methyl-1,2,3-triazole as the starting materialin the procedure of Example 1 givesN-methyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylthio)-ethyl]thiourea.

By the same procedure, using 5-amino-4-(1,2,3-triazole)carboxylic acid,the product isN-methyl-N'-[2-(5-amino-4-(1,2,3-triazolyl)methylthio)ethyl]thiourea.

Similarly, using the following triazolecarboxylic acid compounds:

5-hydroxy-4-(1,2,3-triazole)carboxylic acid (prepared by alkalinehydrolysis of the corresponding ethyl ester)

4,5-(1,2,3-triazole)dicarboxylic acid

3-hydroxy-5-(1,2,4-triazole)carboxylic acid the products are,respectively:

N-methyl-N'-[2-(5-hydroxy-4-(1,2,3-triazolyl)methylthio)ethyl] thiourea

4,5-bis-[2-(N-methylthioureido)ethylthiomethyl]-1,2,3-triazole

N-methyl-N'-[2-(3-hydroxy-5-(1,2,4-triazolyl)methylthio)-ethyl]thiourea.

Reduction of 3-chloro-5-(1,2,4-triazole)carboxylic acid with diboranegives the corresponding 5-hydroxymethyl compound and using this startingmaterial in the procedure of Example 1 givesN-methyl-N'-[2-(3-chloro-5-(1,2,4-triazolyl)methylthio)ethyl]thiourea.

EXAMPLE 176

By the procedure of Example 21, using 3-mercapto-1,2,4-triazole as thestarting material, the product isN-methyl-N'-[3-(3-(1,2,4-triazolyl)thio)propyl]thiourea.

By the same procedure, using 4-mercapto-1,2,3-triazole, the product isN-methyl-N'-[3-(4-(1,2,3-triazolyl)-thio)propyl]thiourea.

EXAMPLE 177N-Methyl-N'-[2-(2-(3-(1,2,4-triazolyl))ethyl)thioethyl]thiourea

Using 3-(2-chloroethyl)-1,2,4-triazole as the starting material in theprocedure of Example 17 gives the title compound.

EXAMPLE 178

Reaction of 3-(2-aminoethyl)thiomethyl-4-methyl-1,2,4-triazole withmethyl isocyanate by the procedure of Example 24 givesN-methyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)-methylthio)ethyl]urea.

Similarly, reacting 4-(2-aminoethyl)thiomethyl-5-methyl-1,2,3-triazole(prepared from 4-hydroxymethyl-5-methyl-1,2,3-triazole by the procedureof Example 1) with methyl isocyanate givesN-methyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)-methylthio)ethyl]urea.

Using ethyl isocyante in place of methyl isocyanate in the aboveprocedure gives the corresponding N-ethyl compounds.

EXAMPLE 179 N-Methyl-N'-[2-(3-(1,2,4-triazolyl)methoxy)ethyl]thiourea

By the procedure of Example 38, using 3-chloromethyl-1,2,4-triazole asthe starting material, the product is the title compound.

EXAMPLE 180

Treatment of 3-(2-aminoethyl)thiomethyl-4-methyl-1,2,4-triazole with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesN-(2-dimethylaminoethyl)-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]thiourea.

By the same procedure, using4-(2-aminoethyl)thiomethyl-5-methyl-1,2,3-triazole (prepared by reacting4-hydroxymethyl-5-methyl-1,2,3-triazole with cysteamine hydrochloride)as the starting material, the product isN-(2-dimethylaminoethyl)-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylthio)ethyl]thiourea.Reacting with hydrobromic acid gives the hydrobromide salt.

EXAMPLE 181

By the procedure of Example 18,3-(2-aminoethyl)-thiomethyl-4-methyl-1,2,4-triazole is reacted withbenzoyl isothiocyanate to giveN-benzoyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]thiourea.Removing the benzoyl group by the procedure of Example 18 givesN-[2-(4-methyl-3-(1,2,4-triazolyl)methylthio)ethyl]thiourea.

By the same procedure reacting4-(2-aminoethyl)-thiomethyl-5-methyl-1,2,3-triazole with benzoylisothiocyanate givesN-benzoyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)-methylthio)ethyl]thioureaand then removing the benzoyl group givesN-[2-(5-methyl-4-(1,2,3-triazolyl)methylthio)-ethyl]thiourea.

EXAMPLE 182

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)-                                 methylthio)ethyl]thiourea  200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

EXAMPLE 183

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)-                                 methylthio)ethyl]thiourea  200 mg.                                            Sucrose                    70 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a triazole ring and Y is NH are exemplifiedby the following examples.

EXAMPLE 184

Using, in the procedure of Example 40, the followingchloroalkyltriazoles (which may be prepared from the correspondinghydroxyalkyltriazoles by treating with thionyl chloride):

3-chloromethyl-1,2,4-triazole

3-(2-chloroethyl)-1,2,4-triazole

3-chloromethyl-4-methyl-1,2,4-triazole

3,5-di(chloromethyl)-1,2,4-triazole

3-chloromethyl-2-benzyl-1,2,4-triazole

3-amino-5-chloromethyl-1,2,4-triazole

3-bromo-5-chloromethyl-1,2,4-triazole

the following products are obtained, respectively:

N-methyl-N'-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]-thiourea

N-methyl-N'-[2-(2-(3-(1,2,4-triazolyl))ethylamino)-ethyl]thiourea

N-methyl-N'-[2-(4-methyl-3-(1,2,4-triazolyl)methylamino)-ethyl]thiourea

3,5-bis-[2-(N-methylthioureido)ethylaminomethyl]-1,2,4triazole

N-methyl-N'-[2-(2-benzyl-3-(1,2,4-triazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-(3-amino-5-(1,2,4-triazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-(3-bromo-5-(1,2,4-triazolyl)methylamino)-ethyl]thiourea.

By the same procedure, using ethyl isothiocyanate in place of methylisothiocyanate, the corresponding N-ethyl compounds are prepared.

Using, in the procedure of Example 40, 3-chloromethyl-1,2,4-triazole and1,3-diaminopropane as the starting materials, the product isN-methyl-N'-[3-(3-(1,2,4-triazolyl)-methylamino)propyl]thiourea.

EXAMPLE 185

In the procedure of Example 40, using the followingchloroalkyltriazoles, prepared from the corresponding hydroxyalkylcompounds by reacting with thionyl chloride:

1-benzyl-4-chloromethyl-1,2,3-triazole

4-chloromethyl-5-methyl-1,2,3-triazole

5-amino-4-chloromethyl-1,2,3-triazole

4-chloromethyl-5-hydroxy-1,2,3-triazole

4,5-di(chloromethyl)-1,2,3-triazole

3-chloro-5-chroromethyl-1,2,4-triazole

3-hydroxy-5-chloromethyl-1,2,4-triazole

the following products are obtained, respectively:

N-methyl-N'-[2-(1-benzyl-4-(1,2,3-triazolyl)methylamino)ethyl]thiourea

N-methyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-(5-amino-4-(1,2,3-triazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-(5-hydroxy-4-(1,2,3-triazolyl)methylamino)-ethyl]thiourea

4,5-bis-[2-(N-methylthioureido)ethylaminomethyl]-1,2,3-triazole

N-methyl-N'-[2-(3-chloro-5-(1,2,4-triazolyl)methylamino)-ethyl]thiourea

N-methyl-N'-[2-(3-hydroxy-5-(1,2,4-triazolyl)methylamino)-ethyl]thiourea.

EXAMPLE 186

Reacting N-(3-(1,2,4-triazolyl)methyl)ethylenediamine, prepared byreacting ethylenediamine with 3-chloromethyl-1,2,4-triazole, with methylisocyanate by the procedure of Example 24, then concentrating andseparating by column chromatography givesN-methyl-N'-[2-(3-(1,2,4-triazolyl)-methylamino)ethyl] urea. Treatmentwith hydriodic acid gives the hydroiodide salt.

EXAMPLE 187

Treating N-(3-(1,2,4-triazolyl)methyl)ethylenediamine with2-dimethylaminoethyl isothiocyanate by the procedure of Example 40, thenconcentrating and separating by column chromatography givesN-(2-dimethylaminoethyl)-N'-[2-(3-(1,2,4-triazolyl)methylamino)ethyl]thiourea.

By the same procedure, usingN-(5-methyl-4-(1,2,3-triazolyl)methyl)ethylenediamine, prepared byreacting ethylenediamine with 4-chloromethyl-5-methyl-1,2,3-triazole,the product isN-(2-diamethylaminoethy)-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)ethyl]thiourea.

EXAMPLE 188

A mixture of 3-chloro-1,2,4-triazole (10.3 g., 0.1 m.) and1,3-diaminopropane (7.4 g., 0.1 m.) in ethanol containing sodiumethoxide is allowed to stand overnight. The solvent is removed to give3-(3-aminopropylamino)-1,2,4-triazole. This intermediate is reacted withmethyl isothiocyanate to giveN-methyl-N'-[3-(3-(1,2,4-triazolyl)amino)propyl]thiourea.

By the same procedure, using 4-chloro-5-methyl-1,2,3-triazole as thestarting material, the intermediate4-(3-aminopropylamino)-5-methyl-1,2,3-triazole and the productN-methyl-N'-[3-(5-methyl-4-(1,2,3-triazolyl)amino)-propyl]thiourea areprepared.

EXAMPLE 189

By the procedure of Example 46, reacting3-(3-aminopropylamino)-1,2,4-triazole with benzoyl isothiocyanate givesN-benzoyl-N'-[3-(3-(1,2,4-triazolyl)amino)propyl]thiourea. Removing thebenzoyl group by the procedure of Example 46 givesN-[3-(3-(1,2,4-triazolyl)amino)propyl]thiourea.

By the same procedure, reacting4-(3-aminopropylamino)-5-methyl-1,2,3-triazole with benzoylisothiocyanate givesN-benzoyl-N'-[3-(5-methyl-4-(1,2,3-triazolyl)amino)-propyl]thiourea andremoving the benzoyl group givesN-[3-(5-methyl-4-(1,2,3-triazolyl)amino)propyl]thiourea.

EXAMPLE 190

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(3-(1,2,4-triazolyl)methyl-                                    amino)ethyl]thiourea       200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Similarly, a capsule is prepared using 200 mg. ofN-methyl-N'-[2-(5-methyl-4-(1,2,3-triazolyl)methylamino)-ethyl]thiourea.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a thiadiazole ring and Y is oxygen or sulphur(sulphur is preferred) are exemplified by the following examples.

EXAMPLE 191N-Methyl-N'-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)-ethyl]thiourea

By the procedure of Example 1, the following intermediate amine salt wasprepared: 2-amino-5-(2-aminoethyl)thiomethyl-1,3,4-thiadiazoledihydrobromide, m.p. 229°-232° C.

Reacting this intermediate amine salt with methyl isothiocyanate by theprocedure of Example 1(ii) gaveN-methyl-N'-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)-ethyl]thiourea,recrystallised from aqueous ethanol, m.p. 143°-145° C. (Found: C, 32.0;H, 5.0; N, 26.7; S, 36.2. C₇ H₁₃ N₅ S₃ requires: C, 32.0; H, 5.0; N,26.6; S, 36.5).

EXAMPLE 192N-Methyl-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)thio)propyl]thiourea

By the procedure of Example 21(i), using2-amino-5-mercapto-1,3,4-thiadiazole as the starting material, thefollowing intermediate dihydrobromide salt was prepared:2-amino-5-(3-aminopropylthio)-1,3,4-thiadiazole dihydrobromide, m.p.185°-188° C.

Reacting this intermediate with methyl isothiocyanate by the procedureof Example 21(ii) gaveN-methyl-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)thio)propyl]thiourea,recrystallised from ethanol-ether, m.p. 109°-110° C. (Found: C, 31.5; H,5.0; N, 26.2; S, 36.1. C₇ H₁₃ N₅ S₃ requires: C, 31.9; H, 5.0; N, 26.6;S, 36.5).

EXAMPLE 193

Using 5-chloro-3-chloromethyl-1,2,4-thiadiazole as the starting materialin the procedure of Example 1, the product isN-methyl-N'-[2-(5-chloro-3-(1,2,4-thiadiazolyl)-methylthio)ethyl]thiourea.

By the same procedure using ethyl isothiocyanate in place of methylisothiocyanate, the corresponding N-ethyl compound is prepared.

Using 5-chloro-3-chloromethyl-1,2,4-thiadiazole and3-mercaptopropylamine as starting materials in the procedure of Example1 givesN-methyl-N'-[3-(5-chloro-3-(1,2,4-thiadiazolyl)methylthio)propyl]thiourea.

EXAMPLE 194N-Methyl-N'-[3-(2-trifluoromethyl-5-(1,3,4-thiadiazolyl)thio)-propyl]thiourea

By the procedure of Example 21, using2-trifluoromethyl-5-mercapto-1,3,4-thiadiazole as the starting material,the product is the title compound.

EXAMPLE 195

Using 2-mercapto-1,3,4-thiadiazole as the starting material in theprocedure of Example 21 givesN-methyl-N'-[3-(2-(1,3,4-thiadiazolyl)thio)propyl]thiourea.

Similarly, using 3-mercapto-1,2,4-thiadiazole as the starting material,the product isN-methyl-N'-[3-(3-(1,2,4-thiadiazolyl)thio)propyl]thiourea.

EXAMPLE 196N-Methyl-N'-[2-(4-(1,2,3,-thiadiazolyl)methylthio)ethyl]thiourea

Using 4-hydroxymethyl-1,2,3-thiadiazole as the starting material in theprocedure of Example 1 gives the title compound.

EXAMPLE 197

Converting 5-methyl-4-(1,2,3-thiadiazole)carboxylic acid to the methylester and reducing the ester with lithium aluminium hydride intetrahydrofuran gives 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole.

Using 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole as the startingmaterial in the procedure of Example 1 givesN-methyl-N'-[2-(5-methyl-4-(1,2,3-thiadiazolyl)methylthio)-ethyl]thiourea.

By the same procedure using the following as starting materials(prepared from the corresponding carboxylic acids by the above processor in the case of the 4-chloro substituted compound by treatment withdiborane):

5-amino-4-hydroxymethyl-1,2,3-thiadiazole

4,5-di(hydroxymethyl)-1,2,3-thiadiazole

4-hydroxy-3-hydroxymethyl-1,2,5-thiadiazole

4-chloro-3-hydroxymethyl-1,2,5-thiadiazole

the following products are obtained, respectively:

N-methyl-N'-[2-(5-amino-4-(1,2,3-thiadiazolyl)methylthio)-ethyl]thiourea

4,5-bis-[2-(N-methylthioureido)ethylthiomethyl]-1,2,3-thiadiazole

N-methyl-N'-[2-(4-hydroxy-3-(1,2,5-thiadiazolyl)methylthio)ethyl]thiourea

N-methyl-N'-[2-(4-chloro-3-(1,2,5-thiadiazolyl)methyl-thio)ethyl]thiourea.

EXAMPLE 198N-Methyl-N'-[2-(2-(2-amino-5-(1,3,4-thiadiazolyl)ethyl)-thioethyl]thiourea

2-Amino-5-(1,3,4-thiadiazole)acetic acid is esterified with anhydrousethanolic hydrogen chloride and the resulting ethyl ester is reducedwith lithium aluminium hydride in tetrahydrofuran to give2-amino-5-(2-hydroxyethyl)-1,3,4-thiadiazole. Treating this hydroxyethylcompound with thionyl chloride gives2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole.

Using 2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole as the startingmaterial in the procedure of Example 17 gives the title compound.

EXAMPLE 199N-Methyl-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)thio)propyl]urea

By the procedure of Example 24,2-amino-5-(3-aminopropylthio)-1,3,4-thiadiazole is reacted with methylisocyanate to give the title compound.

EXAMPLE 200N-Methyl-N'-[2-(5-methyl-4-(1,2,3-thiadiazolyl)methoxy)ethyl]-thiourea

By the procedure of Example 38, using4-chloromethyl-5-methyl-1,2,3-thiadiazole (prepared by reacting4-hydroxymethyl-5 -methyl-1,2,3-thiadiazole with thionyl chloride) asthe atarting material, the title compound is prepared.

EXAMPLE 201

By the procedure of Example 18,2-amino-5-(3-aminopropylthio)-1,3,4-thiadiazole is reacted with benzoylisothiocyanate to giveN-benzoyl-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)thio)propyl]thiourea.Removing the benzoyl group by the procedure of Example 18 givesN-[3-(2-amino-5-(1,3,4-thiadiazolyl)thio)propyl]thiourea. Treatment withhydrochloric acid gives the hydrochloride salt.

EXAMPLE 202N-(2-Dimethylaminoethyl)-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)-thiopropyl]thiourea

Treatment of 2-amino-5-(3-aminopropylthio)-1,3,4-thiadiazole with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 203

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)-                               thio)propyl]thiourea       200 mg.                                            Sucrose                    70 mg.                                             Starch                     25 mg.                                             Talc                       5 mg.                                              Stearic acid               2 mg.                                              ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a thiadiazole ring and Y is NH areexemplified by the following examples.

EXAMPLE 204

Using, in the procedure of Example 40, the followingchloroalkylthiadiazoles (which may be prepared by treating thecorresponding hydroxyalkyl compounds with thionyl chloride):

2-amino-5-chloromethyl-1,3,4-thiadiazole

5-chloro-3-chloromethyl-1,2,4-thiadiazole

4-chloromethyl-1,2,3-thiadiazole

3-chloromethyl-4-hydroxy-1,2,5-thiadiazole

4-chloromethyl-5-methyl-1,2,3-thiadiazole

2-amino-5-(2-chloroethyl)-1,3,4-thiadiazole

4,5-di(chloromethyl)-1,2,3-thiadiazole

the following products are obtained, respectively:

N-methyl-N'-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)ethyl]thiourea

N-methyl-N'-[2-(5-chloro-3-(1,2,4-thiadiazolyl)methylamino)ethyl]thiourea

N-methyl-N'-[2-(4-(1,2,3-thiadiazolyl)methylamino)- ethyl]thiourea

N-methyl-N'-[2-(4-hydroxy-3-(1,2,5-thiadiazolyl)methyl-amino)ethyl]thiourea

N-methyl-N'-[2-(5-methyl-4-(1,2,3-thiadiazolyl)methylamino)ethyl]thiourea

N-methyl-N'-[2-(2-(2-amino-5-(1,3,4-thiadiazolyl))ethylamino)ethyl]thiourea

4,5-bis-[2-(N-methylthioureido)ethylaminomethyl]-1,2,3-thiadiazole.

Using, in the procedure of Example 40,2-amino-5-chloromethyl-1,3,4-thiadiazole and 1,3-diaminopropane as thestarting materials, the product isN-methyl-N'-[3-(2-amino-5-(1,3,4-thiadiazolyl)methylamino)propyl]thiourea.

EXAMPLE 205

Reacting N-(5-amino-2-(1,3,4-thiadiazolyl)methyl)-ethylenediamine,prepared by reacting ethylenediamine with5-amino-2-chloromethyl-1,3,4-thiadiazole, with methyl isocyanate by theprocedure of Example 24, then concentrating and separating the residueby column chromatography givesN-methyl-N'-[2-(5-amino-2-(1,3,4-thiadiazolyl)methylamino)-ethyl]urea.

By the same procedure, using ethyl isocyanate the corresponding N-ethylcompound is prepared.

EXAMPLE 206

Treating N-(5-amino-2-(1,3,4-thiadiazolyl)methy)-ethylenediamine with2-dimethylaminoethyl isothiocyanate by the procedure of Example 40, thenconcentrating and separating by column chromatography givesN-(2-dimethylamino-ethyl)-N'-[2-(5-amino-2-(1,3,4-thiadiazolyl)methylamino)ethyl]-thiourea. Treating with maleicacid in ethanol gives the maleate salt.

EXAMPLE 207

By the procedure of Example 188, 2-bromo-1,3,4-thiadiazole is reactedwith 1,3-diaminopropane to give 2-(3-aminopropylamino)-1,3,4-thiadiazoleand this intermediate is reacted with methyl isothiocyanate to giveN-methyl-N'-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]thiourea.

Similarly, using 3-chloro-1,2,5-thiadiazole as the starting material,the intermediate 3-(3-aminopropylamino)-1,2,5-thiadiazole and theproduct N-methyl-N'-[3-(3-(1,2,5-thiadiazolyl)amino)propyl]thiourea areprepared.

Also, using 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole as the startingmaterial, the intermediate2-(3-aminopropylamino)-5-trifluoromethyl-1,3,4-thiadiazole and theproductN-methyl-N'-[3-(5-trifluoromethyl-2-(1,3,4-thiadiazolyl)amino)propyl]thioureaare prepared.

Reaction of 3-amino-1,2,4-thiadiazole with 3-phthalimidopropyl bromideand hydrazinolysis of the product gives3-(3-aminopropylamino)-1,2,4-thiadiazole and from this intermediateN-methyl-N'-[3-(3-(1,2,4-thiadiazolyl)-amino)propyl]thiourea isprepared.

EXAMPLE 208

By the procedure of Example 46, reacting2-(3-aminopropylamino)-1,3,4-thiadiazole with benzoyl isothiocyanategives N-benzoyl-N'-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]-thiourea.Removing the benzoyl group by the procedure of Example 46 givesN-[3-(2-(1,3,4-thiadiazolyl)amino)propyl]-thiourea.

EXAMPLE 209

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[3-(2-(1,3,4-thiadiazolyl)amino)-                                 propyl]thiourea            200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a benzimidazole ring and Y is oxygen orsulphur (sulphur is preferred) are exemplified by the followingexamples.

EXAMPLE 210

By the process of Example 1 the following intermediate amine salt wasprepared: 2-[(2-aminoethyl)-thiomethyl]benzimidazole dihydrobromide,m.p. 242° -245° C.

Reaction of this intermediate amine salt with methyl isothiocyanate bythe procedure of Example 1(ii) gaveN-methyl-N'-[2-(2-benzimidazolylmethylthio)ethyl]-thiourea,recrystallised from isopropanol/isopropyl acetate, m.p. 157° -159° C.(Found: C, 51.3; H, 5.8; N, 19.9; S, 22.5. C₁₂ H₁₆ N₄ S₂ requires: C,51.4; H, 5.8; N, 20.0; S, 22.9).

EXAMPLE 211 N-Methyl-N'-[2-(2-(2-benzimidazolyl)ethyl)thioethyl]thiourea

Using 2-(2-chloroethyl)benzimidazole, prepared by treating2-(2-hydroxyethyl)benzimidazole with thionyl chloride, as the startingmaterial in the procedure of Example 17 gives the title compound.

EXAMPLE 212 N-Methyl-N'-[2-(2-benzimidazolylmethylthio)ethyl]urea

By the procedure of Example 24,2-[(2-aminoethyl)thiomethyl]benzimidazole is reacted with methylisocyanate to give the title compound.

EXAMPLE 213

Using 2-chloromethylbenzimidazole (prepared by reacting2-hydroxymethylbenzimidazole with thionyl chloride) as the startingmaterial in the procedure of Example 38 givesN-methyl-N'-[2-(2-benzimidazolylmethoxy)ethyl]thiourea.

Using 2-chloromethylbenzimidazole as the starting material in theprocedure of Example 28 givesN-methyl-N'-[3-(2-benzimidazolylmethoxy)propyl]thiourea.

EXAMPLE 214

By the procedure of Example 21, using 2-mercaptobenzimidazole as thestarting material, N-methyl-N'-[3-(2-benzimidazolylthio)propyl]thioureais obtained. Reacting with hydrobromic acid gives the hydrobromide salt.

Using ethyl isothiocyanate in place of methyl isothiocyanate in theabove procedure gives the corresponding N-ethyl compound.

EXAMPLE 215

Benzoyl isothiocyanate is reacted with2-[(2-amincethyl)thiomethyl]benzimidazole by the procedure of Example 18to give N-benzoyl-N' -[2-(2-benzimidazolylmethylthio)ethyl]thiourea.Removing the benzoyl group by the procedure of Example 18 givesN-[2-(2-benzimidazolylmethylthio)ethyl]thiourea.

EXAMPLE 216N-(2-Dimethylaminoethyl)-N'-[2-(2-benzimidazolylmethylthio)ethyl]thiourea

Treatment of 2-[(2-aminoethyl)thiomethyl]benzimidazole with2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 givesthe title compound.

EXAMPLE 217

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-benzimidazolylmethylthio)-                                  ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a benzimidazole ring and Y is NH areexemplified by the following examples.

EXAMPLE 218

Using 2-chloromethylbenzimidazole in the procedure of Example 40 givesN-methyl-N'-[2-(2-benzimidazolylmethyl-amino)ethyl]thiourea.

Similarly, using 2-(2chloroethyl)benzimidazole, the product isN-methyl-N'-[2-(2-(2-benzimidazolyl)ethylamino)-ethyl]thiourea. Reactingwith hydrochloric acid gives the hydrochloride salt.

EXAMPLE 219 N-Methyl-N'-[2-(2-benzimidazolylmethylamino)ethyl]urea

Reacting N-(2-benzimidazolylmethyl)ethylenediamine, prepared by reactingethylenediamine with 2-chloromethylbenzimidazole by the procedure ofExample 40, with methyl isocyanate by the procedure of Example 24 andthen concentrating and separating the residue by column chromatographygives the title compound.

Using 2-chloromethylbenzimidazole and 1,3-diaminopropane as the startingmaterials in the procedure of Example 40 gives N-methyl-N'-[3-(2-benzimidazolylmethylamino)propyl]thiourea.

EXAMPLE 220 N-Methyl-N'-[3-(2-benzimidazolylamino)propyl]thiourea

Using 2-aminobenzimidazole as the starting material in the procedure ofExample 53 gives 2-(3-aminopropylamino)-benzimidazole as theintermediate and reacting that intermediate with methyl isothiocyanategives the title compound.

EXAMPLE 221N-(2-Dimethylaminoethyl)-N'-[2-(2-benzimidazolylmethylamino)ethyl]thiourea

N-(2-Benzimidazolylmethyl)ethylenediamine, prepared by reactingethylenediamine with 2-chloromethylbenzimidazole by the procedure ofExample 40, is reacted with 2-dimethylaminoethyl isothiocyanate by theprocedure of Example 40 to give the title compound.

EXAMPLE 222

Reacting 2-(3-aminopropylamino)benzimidazole with benzoyl isothiocyanateby the procedure of Example 46 givesN-benzoyl-N'-[3-(2-benzimidazolylamino)propyl]thiourea.

Removing the benzoyl group by the procedure of Example 46 givesN-[3-(2-benzimidazolylamino)propyl]thiourea. Reacting with hydrobromicacid gives the dihydrobromide salt.

EXAMPLE 223

    ______________________________________                                        Ingredients                Amounts                                            ______________________________________                                        N-Methyl-N'-[2-(2-benzimidazolylmethylamino)-                                 ethyl]thiourea             200 mg.                                            Lactose                    100 mg.                                            ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinering and Y is oxygen or sulphur (sulphur is preferred) are exemplifiedby the following examples.

EXAMPLE 224N-Methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)-methylthio)ethyl]thiourea

A solution of 1.58 molar n-butyl lithium in n-hexane (49 ml.) was addedover 0.5 hour to a stirred solution of5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60°under nitrogen. After 3 hours, gaseous formaldehyde generated by thethermal condensation of paraformaldehyde (6.9 g.) was passed into thered solution. The mixture was allowed to warm to room temperatureovernight, acidified with hydrochloric acid and extracted withchloroform. The aqueous layer was basified with an excess of saturatedsodium carbonate solution and extracted with chloroform. Concentrationand recrystallisation of the residue from ethanol-ethylacetate-petroleum ether afforded3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (7.7 g.), m.p.188° -199° .

Reacting 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo-[1,5-a]pryidine withcysteamine hydrochloride by the procedure of Example 1(i)(a) gave thefollowing intermediate amine salt:3-[(2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinedihydrobromide.

Reacting the above prepared intermediate amine salt with methylisothiocyanate by the procedure of Example 1(ii) gaveN-methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]thiourea,recrystallised from isopropyl acetate/ethyl acetate, m.p. 105° -106° C.(Found:

50.7; H, 7.1; N, 19.6; S, 22.3. C₁₂ H₂₀ N₄ S₂ requires: C, 50.7; H, 7.1;N, 19.7; S, 22.5). EXAMPLE 225

By the procedure of Example 28, using3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, prepared byreacting the 3-hydroxymethyl compound with thionyl chloride, as thestarting material,N-methyl-N'-[3-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methoxy)propyl]thioureais prepared. Reacting with hydriodic acid gives the hydroiodide salt.

EXAMPLE 226

By the procedure of Example 24,3-[(2-aminoethyl)-thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridineis reacted with methyl isocyanate to giveN-methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]urea.

By the same procedure, using ethyl isocyanate the corresponding N-ethylcompound is obtained.

EXAMPLE 227

By the procedure of Example 18, 3-[(2-aminoethyl)-thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine is reacted with benzoylisothiocyanate to giveN-benzoyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)-ethyl]thiourea.Removing the benzoyl group by the procedure of Example 18 givesN-[2-(3-(5,6,7,8-tetrahydroimidazo(1,5-a]-pyridyl)methylthio)ethyl]thiourea.

EXAMPLE 228N-(2-Dimethylaminoethyl)-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylthio)ethyl]thiourea

Treatment of3-[(2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridinewith 2-dimethylaminoethyl isothiocyanate gives the title compound.

EXAMPLE 229

    ______________________________________                                        Ingredients                 Amounts                                           ______________________________________                                        N-Methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo-                                 [1,5-a]pyridyl)methylthio)ethyl]thiourea                                                                  200 mg.                                           Lactose                     100 mg.                                           ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

Compounds of formula I wherein A is such that there is formed togetherwith the carbon atom shown a 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinering and Y is NH are exemplified by the following examples.

EXAMPLE 230

Using 3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, preparedby treating the corresponding 3-hydroxymethyl compound with thionylchloride, as the starting material in the procedure of Example 40 givesN-methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)-methylamino)ethyl]thiourea.Treating with hydrobromic acid gives the hydrobromide salt.

By the same procedure, using ethyl isothiocyanate in place of methylisothiocyanate, gives the corresponding N-ethyl compound.

EXAMPLE 231N-Methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)-methylamino)ethyl]urea

N-(3-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridyl)-methyl)ethylenediamine,prepared by reacting ethylenediamine with3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine by the procedureof Example 40, is reacted with methyl isocyanate by the procedure ofExample 24 to give, after concentrating and separating by columnchromatography, the title compound.

EXAMPLE 232N-(2-Dimethylaminoethyl)-N'-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methylamino)ethyl]thiourea

ReactingN-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]-pyridyl)methyl)ethylenediaminewith 2-dimethylaminoethyl isothiocyanate by the procedure of Example40(a)(ii) gives the title compound.

EXAMPLE 233

By the procedure of Example 46,N-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)methyl)ethylenediamine isreacted with benzoyl isothiocyanate and the benzoyl group is removed togiveN-[2-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]-pyridyl)methylamino)ethyl]thiourea.

EXAMPLE 234N-Methyl-N'-[3-(3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridyl)-methylamino)propyl]thiourea

Using as the starting materials in the procedure of Example 40,1,3-diaminopropane and3-chloromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, the titlecompound is prepared.

EXAMPLE 235

    ______________________________________                                        Ingredients               Amounts                                             ______________________________________                                        N-Methyl-N'-[2-(3-(5,6,7,8-tetrahydroimidazo-                                 [1,5-a]pyridyl)methylamino)ethyl]thiourea                                                               200 mg.                                             Lactose                   100 mg.                                             ______________________________________                                    

The ingredients are mixed and filled into a hard gelatin capsule.

The pharmaceutical compositions prepared as in the foregoing examplesare administered to a subject within the dose ranges given hereabove toinhibit H-2 histamine receptors.

In the forgoing examples, the temperatures are in degrees Centigrade.

What we claim is:
 1. A pharmaceutical composition to inhibit H-2histamine receptors comprising a pharmaceutical carrier and in aneffective amount to inhibit said receptors a heterocyclic compound ofthe formula: ##STR28## wherein A is such that there is formed togetherwith the carbon atom shown an unsaturated heterocyclic nucleus, saidunsaturated heterocyclic nucleus being an imidazole or pyrazole ring; X₁is hydrogen, lower alkyl, hydroxyl, trifluoromethyl, benzyl, halogen,amino or ##STR29## X₂ is hydrogen or when X₁ is lower alkyl, lower alkylor halogen; k is 0 to 2 and m is 2 or 3, provided that the sum of k andm is 3 or 4; Y is oxygen, sulphur or NH; E is oxygen or sulphur; and R₁is hydrogen, lower alkyl, benzoyl or di-lower alkylamino-lower alkyl ora pharmaceutically acceptable addition salt thereof with the provisothat X₁ is ##STR30## only when Y and E are sulphur and R₁ is methyl andwith the proviso that when X₁ is other than hydrogen or lower alkyl andX₂ is other than hydrogen, X₁ and X₂ are attached at carbon atoms.
 2. Apharmaceutical composition of claim 1 in which the heterocyclic compoundis N-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea. 3.A pharmaceutical composition of claim 1 in which the pharmaceuticalcomposition is in the form of a tablet or capsule.
 4. A pharmaceuticalcomposition of claim 1 in which the heterocyclic compound is present inan amount of from about 50 mg. to about 250 mg.
 5. A method ofinhibiting H-2 histamine receptors which comprises administering to ananimal in need of inhibition of said receptors in an effective amount toinhibit said receptors a heterocyclic compound of the formula: ##STR31##wherein A is such that there is formed together with the carbon atomshown an unsaturated heterocyclic nucleus, said unsaturated heterocyclicnucleus being an imidazole or pyrazole ring; X₁ is hydrogen, loweralkyl, hydroxyl, trifluoromethyl, benzyl, halogen, amino or ##STR32## X₂is hydrogen or when X₁ is lower alkyl, lower alkyl or halogen; k is 0 to2 and m is 2 or 3, provided that the sum of k and m is 3 or 4; Y isoxygen, sulphur or NH; E is oxygen or sulphur; and R₁ is hydrogen, loweralkyl, benzoyl or di-lower alkylamino-lower alkyl or a pharmaceuticallyacceptable addition salt thereof with the proviso that X₁ is ##STR33##only when Y and E are sulphur and R₁ is methyl and with the proviso thatwhen X₁ is other than hydrogen or lower alkyl and X₂ is other thanhydrogen, X₁ and X₂ are attached at carbon atoms.
 6. A method of claim 5in which the heterocyclic compound isN-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiourea.
 7. Amethod of claim 5 in which the heterocyclic compound is administeredorally.
 8. A method of claim 5 in which the heterocyclic compound isadministered in a daily dosage regimen of from about 150 mg. to about1000 mg.
 9. A method of inhibiting gastric acid secretion whichcomprises administering to an animal in need of inhibition of gastricacid secretion in an effective amount to inhibit gastric acid secretiona heterocyclic compound of the formula: ##STR34## wherein A is such thatthere is formed together with the carbon atom shown an unsaturatedheterocyclic nucleus, said unsaturated heterocyclic nucleus being animidazole or pyrazole ring; X₁ is hydrogen, lower alkyl, hydroxyl,trifluoromethyl, benzyl, halogen, amino or ##STR35## X₂ is hydrogen orwhen X₁ is lower alkyl, lower alkyl or halogen; k is 0 to 2 and m is 2or 3, provided that the sum of k and m is 3 or 4; Y is oxygen, sulphuror NH; E is oxygen or sulphur; and R₁ is hydrogen, lower alkyl, benzoylor di-lower alkylamino-lower alkyl or a pharmaceutically acceptableaddition salt thereof with the proviso that X₁ is ##STR36## only when Yand E are sulphur and R₁ is methyl and with the proviso that when X₁ isother than hydrogen or lower alkyl and X₂ is other than hydrogen, X₁ andX₂ are attached at carbon atoms.
 10. A method of claim 9 in which theheterocyclic compound isN-methyl-N'-[2-((5-methyl-4-imidazolyl)methylthio)-ethyl]thiourea.